Regulations of hpa by cytokines

Addis Ababa University
School of health sciences
Department of physiology
Regulation of the Hypothalamic-Pituitary-Adrenal Axis
by Cytokines: Actions and Mechanisms
A Review
By
Girmay Fitiwi
April, 2012

I | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s
Acknowledgments
I would like to extend my deepest gratitude and appreciation to my advisor Dr. Getahun Shibru
for his excellent valuable, careful reviewing and scientific comments of the manuscript. I also
thank AAU digital libraries for their full resources of journals and free internet access.
Finally I would like to thank to my instructors, my family and my colleagues.

II | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s
Table of Contents
Contents Page
Acknowledgments ......................................................................................................... I
Table of Contents ........................................................................................................ II
List of Acronyms ........................................................................................................ IV
List of Figures ........................................................................................................... VII
Summary .................................................................................................................VIII
1. Introduction............................................................................................................... 1
2. Over View of Cytokines ............................................................................................ 2
2.1. IL-1, IL-6, and TNF ..................................................................................... 7
3. Hypothalamic-pituitary-adrenal axis ....................................................................... 9
4. Cytokines Effect on the Secretory Activities of HPA axis ..................................... 11
5. Cytokine Actions on the Central Nervous System, Pituitary, and Adrenal.......... 12
6. Evidence that Cytokines Activate the Hypothalamic-Pituitary-Adrenal Axis
Primarily at the Level of the Central Nervous System ........................................... 13
6.1 Cytokine receptors within the CNS .............................................................. 13
6.1.1. IL-1 Receptors in the CNS........................................................ 14
6.1.2. IL-6 Receptors in the CNS........................................................ 15
6.1.3. TNF Receptors in the CNS ....................................................... 16
6.2. Cytokine Expression in the CNS.................................................................... 17
6.2.1. Basal Expression ........................................................................ 17
6.2.2 Induced Expression ...................................................................... 18
6.3. Cytokine Actions at the Level of the CNS...................................................... 20

III | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s
7. Evidence for Direct Effects of Cytokines Pituitary Adrenocorticotropic
Hormone Secretion................................................................................................. 22
7.1. Cytokine Receptors within the Pituitary...................................................... 22
7.2. Cytokine Expression in the Pituitary ........................................................... 23
7.3. Direct Effects of Cytokines on Pituitary ACTH........................................... 24
8. Evidence for Direct Actions of Cytokines on Adrenal Glucocorticoids
Secretion ................................................................................................................. 25
8.1. Cytokine Expression in the Adrenal Gland.................................................. 25
8.2. Direct effects of cytokines on Adrenal Glucocorticoids Secretion ............... 26
9. Mechanisms OF Hypothalamic Pituitary Adrenal Axis Activation by
Interleukin-1........................................................................................................ 27
9.1. Direct Actions of IL-1 on Pituitary and Adrenal.......................................... 28
9.2. Penetration of Cytokines into Brain............................................................. 29
9.3. Cytokines and Blood-Brain Barrier Integrity............................................... 31
9.4. Carrier-Mediated Transport of Cytokines across the Blood-Brain Barrier.... 31
9.5. Role of Readily Diffusible Intermediates .................................................... 32
9.6. Cytokines Actions at Circumventricular Organs.......................................... 32
10. Conclusions and prospective Studies ................................................................... 33
11. References

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List of Acronyms
ACTH Adrenocorticotropin hormone
aFGF acidic fibroblast growth factor
AP Area Postrema
AV3V Antero Ventricular Third Ventricle
AVP Arginine Vasopressin
BBB Blood Brain Barrier
BDNF Brain-derived neurotrophic factor
bFGF basic fibroblast growth factor
CAMP Cyclic Adenomono Phosphate
Cinc cytokine-induced neutrophil chemo attractant
CNS Central Nervous System
CNTF Ciliary Neurotropic Factor
CRH corticotropic releasing factor/hormone
CSF Colony Stimulating Factor
CT-1 Cardiotropin1
CVO Circumventricular organs
EGF Epidermal Growth Factor
GC Glucocorticosteroids
G-CSF Granulocyte Colony Stimulating Factor
GDNF Glial Derived Neurotrophic Factor
GM-CSF Granulocyte-Macrophage Colony Stimulating Factor

V | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s
gp130 Glyco protein 130
gro Growth-Related Oncogene
HPA Hypothalamic pituitary adrenal
IH Inferior Hypophysial
ICE Interleukin Converting Enzyme
IFN-α/ β/ γ Interferon alpha/beta/gamma
IGF insulin-like growth factor
IL Interleukin
IL-1R1/ IL-1R2 interleukin receptor1/2
IL-Ira Interleukin-1 receptor antagonist
IP Intraperitoneal
IV Intravenous
JAK Janus kinase
LIF Leukemia Inhibitory Factor
LPs Lipopolysaccharides
MCSF Macrophage Colony Stimulating Factor
ME Median Eminence
MIF Macrophage migrating inhibitory factor (MIF)
MIP Macrophage inflammatory protein
mRNA Messenger Ribonucleic Acid
NAP Neutrophil Activating Protein
NFkB Nuclear factor KB

VI | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s
NGF Nerve Growth Factor
NT Neurotrophin
OM Oncostatin M
OVLT Organum Vascularis Lateral Terminalis
PACPA Pituitary Adenylate Cyclase Activating Polypeptide
PCR Polymerization Chain Reaction
PDGF Platelet-Derived Growth Factor
POMC proopiomelanocortin
PVN paraventricular nucleus
RANTES Regulated upon activation Normal and Secreted
RNA Ribo Nucleic Acid
SH Superior Hypophysial
SCF Stem Cell Factor
SFO Subfornical organ
STAT Signal transducer and activator of transcription protein
TGF Transforming Growth Factor
TNFR1/R2 Tumor Necrosis Factor Receptor1/2
TNF-α/ β Tumor Necrosis Factor alpha/beta
VIP Vasoactive Intestinal Peptide

VII | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s
List of Figures
Figure 1. Reciprocal Relationship between the CNS and Immune System…….1
Figure 2. Cytokines Family………6
Figure 3. Functional Anatomy of Hypothalamic-Pituitary-Adrenal Axis …….10
Figure 4. Proposed models by which interleukin-1 influences secretory activity of hypothalamic
Pituitary- Adrenal Axis….30
List of Tables
Table 1. Cytokines Family……5

VIII | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s
Summary
Cytokines are low molecular, soluble glycoprotein intracellular mediators produced ubiquitous-
ly during inflammation, infection, psychological and physical stress to maintain homeostasis
mechanisms of the body by coordinating neuroendocrine immune system. Furthermore cytokines
are not only important during threating conditions, but also important in normal physiological
process such as in sleep, exercise and ovulation in very low concentration.
Several cytokine families increase the secretory activity of the HPA axis. Constitutive expression
of cytokines, even though at low levels, has been reported also on most cell types throughout the
brain and in the hypothalamus-pituitary-adrenal (HPA) axis, and these often show rapid up-
regulation in response to injury and inflammation. In rodent brain tissues, the highest densities
of cytokine receptors occur in the hippocampus and hypothalamus. Cytokine receptors are also
widely expressed within anterior pituitary cells.
Almost all proinflammatory cytokines stimulate the HPA axis in vivo and proopiomelanocortin
(POMC) expression in vitro. HPA stimulation occurs either at the hypothalamic level (IL-1β, TN
F α), inducing CRH gene expression and CRH release or at the level of pituitary corticotrophs.
In addition to CRH, inflammatory cytokines also trigger central ACTH secretagogues such as
noradrenaline, pituitary adenylate cyclase-activating polypeptide (PACAP), vasopressin and
other cytokines. Proinflammatory cytokines may impair feedback regulation of the HPA axis by
attenuating glucocorticoids receptor function. By stimulating the HPA axis and release of ant-
inflammatory glucocorticoids, cytokines can antagonize their own proinflammatory action.
Key words: adrenal gland: anti inflammatory: blood brain barrier (BBB): central nervous sys-
tem: circum ventricular organs: cytokines: interleukins: proinflammatory: lipopolysaccharides:
paraventricular: pituitary.

1 | R e g u l a t i o n s o f H P A a x i s b y c y t o k i n e s
1. Introduction
The nervous, endocrine and immune systems are anatomically and functionally interconnected.
These organ systems both express and respond to a large number of common regulatory mole-
cules including steroids, neuropeptide, cytokines and neurotransmitters, which provide the mo-
lecular basis for integrated, bidirectional coordinated neuroendocrine-immune responses to ho-
meostasis disturbances induced by stress, inflammation or infection. By the 1980s, the immune
system was known to synthesize and secrete a number of chemical messengers, which were
known generically as cytokines (Besedovsky et al., 1986,Turnbull and Catherine, 1999).
Cytokines are low molecular-weight proteins or glycoproteins that were initially thought to be
restricted to the immune system as mediators of communication between immune cells. Howev-
er, it soon becomes evident that cytokines exert profound effect on the key functions of the cen-
tral nervous, such as food intake, fever, neuroendocrine regulation, long-term potentiation and
behavior. It was reported that cytokines were also produced by brain cells and that they interact
closely with neurohormones and neurotransmitters. Furthermore the regulatory pathways that
control the immune system include the autonomic nervous system and neuro endocrine hor-
mones such as CRH and substance P (Ziemssen and kern, 2007).
FIG.1 Reciprocal Relationship between the CNS and Immune System (source: John Haddad et al., 2002)

This paper attempts to review the role of cytokines in regulation of hypothalamic pituitary adren-
al axis, briefly on the effects of cytokine on hypothalamic neurons, which have response for se-
cretion of CRH, on the adenohypophysis of Pars dsitalis related to ACTH and the direct effect on
adrenal cortex.
2. Over View of Cytokines
Cytokines are a diverse group of pleiotropic1
and redundant2
soluble polypeptides that are rapid-
ly produced by immune cells in response to tissue injury, infection or inflammation. Furthermore
it mediates growth, differentiation and function of many different cell types (Turnbull and
Rivier, 1999). Constitutive expression of cytokines, even though at low levels, has been report-
ed also on most cell types throughout the brain and in the hypothalamus-pituitary-adrenal (HPA)
axis, and these often show rapid up-regulation in response to injury and inflammation (Anastasia
et al., 2004) . In rodent brain tissues, the highest densities of cytokine receptors occur in the hip-
pocampus and hypothalamus (Vitkovic et al., 2000). Cytokine receptors are also widely ex-
pressed within anterior pituitary cells (Ray and Melmed, 1997,Turnbull and Rivier, 1999).
The classification of cytokines into families has proven somewhat arbitrary. With the exception
of a few homologous peptides (e.g., IL-1α and 1β; interferon α and β; and tumor necrosis factor,
α, β) most cytokines share little sequence similarity. Consequently, classification of cytokines
has been based on functional attributes, target receptors, or cells of origin. Most commonly cyto-
kines have been classified into families of interleukins 1 to 13 (IL-1 to -13), tumor necrosis fac-
tor α and β, transforming growth factor β, interferon α, β, and γ, chemokines, hematopoietins (or
neuropoietins) and colony-stimulating factor. Growth factor and neutrotropins are categorized as
cytokines because of their similar action particularly within central nervous and peripheral nerv-
ous system. All of these factors are polypeptides and act on a variety of target cells through spe-
cific plasma membrane receptor proteins in a non-antigen-specific manner and a typical action is
defined as autocrine or paracrine, but not commonly considered endocrine (Simon et al., 1994).
1
Any given cytokine may have different biological effect on different target cells.
2
Two or more cytokine may mediate similar functions.

One of the striking futures of cytokines is pleiotropy and redundancy (Cohen MC and Cohen S,
1996). Cytokine pleiotropy presumably relates to the wide spread distribution of cytokine recep-
tors on numerous cell types and their ability of signal transduction mechanisms activated by cy-
tokines to alter the expression of a wide variety of target genes. The functional redundancy of
various cytokines has at least partially been explained by the identification and molecular clon-
ing of many cytokine receptors. Some, although certainly not all, cytokine receptors consist of a
multiunit complex, including a cytokine-specific ligand binding component and a class specific
signal transduction unit (kishimoto et al.,1995, Sato and Miyajim,1994). In addition to the gp130
signaling cytokines, common receptor subunits have also been demonstrated for IL-2, IL-4, and
IL-7 (Sato and Miyajima,1994) and also for IL-3, IL-5, and granulocyte-macrophage CSF which
share the signal transduction subunit KH7 (Miyajima et al.,1992). However, cytokine redundan-
cy cannot be totally explained by the sharing of receptor subunits, since a number of cytokines,
for example, IL-1, IL-6, and TNF-α, have many common biological activities despite the utiliza-
tion of distinct cell surface receptors.
A further striking feature of cytokines is the multiple interactions between different individual
cytokines. Many types of interactions are apparent, including stimulatory or inhibitory actions at
the level of cytokine synthesis. For example, the proinflammatory cytokines TNF-α and IL-1
potently stimulate the production of a number of other cytokines, including each other, as well as
IL-6, IL8, IL-9, macrophage inflammatory protein (MIP), and CSF (Dinarello,1991). In contrast,
anti-inflammatory cytokines such as IL-4, IL-10, and IL-13 abrogate the production of many
proinflammatory cytokines (e.g., IL-1, IL-8, IL-12, TNF α, IFN γ, and CSF) (Burger and Dayer,
1995). The great prosperity for cytokine-cytokine interactions is illustrated by the large number
of different cytokines that may be produced by a single threat to cellular/ tissue homeostasis. For
example, endotoxemia has been reported to cause the increased synthesis and secretion of IL-1a,
IL-1b, IL-1ra, IL-6, IL-8, IL-10, IL-12 TNF α, MIP, macrophage migrating inhibitory factor
(MIF), IFN γ, leukemia inhibitory factor (LIF), and granulocyte-macrophage and CSF. It is
therefore apparent that during the course of a threat to tissue homeostasis, the physiological out-
come is determined by the net effect of the interactions between a numbers of cytokines.

Cytokines may play a role in some physiological processes in very low concentration such as in
sleep (Szafarczyk et al., 1988) exercise (Cannon and Dinarello, 1985) and ovulation (Adashi,
1997). However cytokine production increases markedly during tissue stress produced by diverse
cellular challenges, including periods of rapid cellular growth, tissue remodeling, disease, infec-
tion, or trauma. The particular cytokines produced in response to a threat to tissue homeostasis
depends on the nature of the threat (e.g., bacterial, viral, inflammatory), the cellular or tissue type
being threatened, the hormone milieu, and to a large extent the profile of other cytokines that are
being produced.

Table1. Cytokines Family (Source: Younis and Abou El-Ezz, 2010)
Family Members Major ascribed actions
Interleukins Il-1 to IL-18 Categorization as an IL does not im-
ply function; IL have numerous and
diverse Immuno regulatory actions;
some IL have clearly
proinflammatory actions (e.g., IL-1a,
IL-1b, IL-8, IL-9), whereas others
have anti-inflammatory effects (e.g.,
IL-1ra, IL-4, IL-10, IL-13). Many IL
also induce systemic aspects of acute
phase response (e.g., fever)
Tumor necrosis factor TNF α, TNF β Tumor cytotoxicity; broad-ranging
immunologic activities; induction of
many other cytokines ,
immunostimulant , proximal mediator
of inflammatory response
Interferon IFN α,β,γ Inhibit viral replication; regulation of
specificity of immune responses
Chemokines IL-8/cinc/gro/NAP-1,
MIP-1a,-b,RANTES
Chemotaxis; activation of cells at in-
flammatory sites
Hematopoietins IL-6,CNTF,LIF,OM,IL-
11,CT-1
All Utilize gp 130 receptor subunit
for signaling; various action on B
cells and other immuno regulatory
actions; promote survival of neurons
Colony stimulating factors G-CSF,M-CSF,GM-CSF,
SCF,Il-3,IL-5
Promotion of growth and differentia-
tion of multi potential progenitor cells
in bone marrow; increase numbers of,
or enhance activity of, cells of granu-
locyte, macrophage, and eosinophil
lineages
Neurotrophins NGF,BDNF,GDNF,NT-
3,NT-6
Neuronal growth and differentiation
Growth Factors IGFI,IGFII,aFGF,bFGF,PD
GF,TNF β, activin
Cell growth and differentiation

FIG.2 Cytokines Family (Source: Younis and Abou El-Ezz, 2010)
Although many different cytokines have been shown to influence HPA axis secretory activity, by
far the majority of studies have focused on the cytokines IL-1, IL-6 and TNFα herein, gives a
brief discussion on the structure, biosynthesis, and receptors of these three cytokines.
Cytokines
Anti-inflammatory cytokines
Up-regulation of the in-
flammatory response
IL-1
IL-6
TNF-a
IFN-a
IFN-b
Up-regulation of acute
phase reactants
IL-1
IL-6
IL-11
TNF-α
IFN-γ
TNF-β
Inhibition of pro-
inflammatory cytokines
IL-1
IL-6
IL-13
Inhibition of NO syn-
thase activity
IL-10
Pro-Inflammatory cytokines
Stimulation of pro-
inflammatory cytokines
IL-12
Chemoattractant IL 8
TGF-β inhibits T cell
proliferation, enhances
collagen production and
facilitates the isolation of
the inflammatory focus

2.1. IL-1, IL-6, and TNF
Interleukin -1 is the prototype of the pro-inflammatory cytokines in that it induces the expression
of a variety of genes and the synthesis of several proteins that, in turn, induce acute and chronic
inflammatory changes. IL-1 is also the prototypic alarm cytokine in that it brings about increases
in a variety of defense mechanisms (Dinarello, 1991).
There are three distinct glycoproteins that constitute the IL-1 family. The two agonists (IL-1a,
IL-1b) and an endogenous antagonist at IL-1 receptors (IL-1ra). IL-1a and IL-1b share 25% se-
quence homology, are distinct gene products, and exhibit the same activities in numerous bio-
logical test systems (Dinarello, 1991). Both are synthesized as 31-kDa3
precursor molecules.
Pro-IL-1b is biologically inactive and requires proteolytic cleavage by the IL-1b converting en-
zyme (ICE, also known as caspase-1) (Keane et al., 1993). In addition an endogenous antagonist
at IL-1 receptors (IL-1ra) shares significant homology with IL- 1a and IL-1b, binds IL-1 recep-
tors, but lacks intrinsic biological activity (Hannum et al., 1990).
The IL-1 receptor is expressed in most cells and tissues, although often at very low levels (<100
binding sites per cell).There are two distinct mammalian membrane-bound IL-1 receptors, desig-
nated IL-1R1 and IL-1R2 and one receptor accessory protein (Greenfeder et al., 1991). Both re-
ceptors are glycoproteins belonging to the immunoglobulin supergene family and possess a sin-
gle transmembrane domain. Each receptor binds IL-1a, IL- 1b, and IL-1ra, but with differing af-
finities. It has been proposed that the biological actions of IL-1 are mediated exclusively through
IL-1R1 (Labow et al., 1997), with IL-1R2 functioning solely as a decoy receptor that limits the
availability of IL-1 for interaction with IL-1R1 (Colotta et al., 1993).
3
A unit that is used for indicating mass on atomic or molecular scale. It is defined as one twelfth
of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground
state and has a value of 1.660 538 921(73) x 10-27
Kg.

Tumor necrosis factor occurs in α and β forms, which share approximately 50% homology.
TNFα (also known as cachectin) is expressed on a wide variety of hemopoietic and non
hemopoietic cells as a 26-kDa membrane-associated molecule. This can be processed to give a
secreted 17-kDa soluble form that mediates a range of inflammatory and cellular immune re-
sponses.
Actions of TNFα are exerted through interactions with two distinct receptors: the 55-kDa (TNF-
R1) and 75- kDa (TNF-R2) receptors. These two receptors are both transmembrane proteins with
a single transmembrane span and are expressed at low levels on most cell types. Although the
extracellular domains of these two receptors show a similar architecture, the intracellular do-
mains of these two receptors bear no significant homology, suggesting that they utilize separate
signaling path ways (Lewis et al., 1991).
Binding of TNF to either receptor activates the proinflammatory transcription factor NFkB. In
the case of TNF-R2, signal transduction occurs via heteterodimerization of the receptor with two
TNF-R2 associated factors, TRAF1 and TRAF2, and it is TRAF2 that appears to mediate TNF-
R2-induced activation of NFkB. In contrast, TNF-R1, upon ligand binding recruits a protein
called TRADD, which causes apoptosis via an ICE-like protease. This explains why TNF-R1,
but not TNF-R2, causes apoptosis. However, the NH2-terminal domain of TRADD interacts di-
rectly with TRAF2, and over expression of a dominant negative TRAF2 blocks not only TNF-R2
but also TNF-R1-induced NFkB activation. Thus activation of the two TNF receptors elicits sep-
arate signaling pathways that can interact with one another, thus explaining the distinct and over-
lapping signals generated by the two TNF receptors. Tumor necrosis factor β (lymphotoxinα) is
produced predominantly by activated lymphocytes.
Interleukin-6 is a single 21 to 28kDa glycoprotein produced by both lymphoid and non lymphoid
cells and regulates immune responses, acute-phase protein synthesis, and hematopoiesis. Human
IL-6 is synthesized as a precursor polypeptide of 212 amino acids that is processed by cleavage
of a 28amino acid NH2-terminal signal sequence into a mature form of 184 amino acids (Turn-
bull and Catherine, 1999).
Interleukin-6 belongs to a family of cytokines that includes ciliary neurotropic factor (CNTF),
oncostatin M (OM), LIF, IL-11, and cardiotropin1 (CT-1), which shares a common signal-

transducing mechanism (Kishimoto et al., 1995). All these cytokines are bound by receptors that
interact with the common cell-surface protein gp130. Ligand-receptor complexes that share
gp1304
trigger signaling by the formation of either homodimers of gp130 or hetero dimers be-
tween gp130 and LIFR. Regarding IL-6, signaling is initiated by the homodimerization of gp130
induced by the interaction with the IL-6/IL-6Rα complex. Either homodimerization of gp130 or
heterodimerization of gp130 with LIFR activates JAK kinases, followed by the tyrosine-specific
phosphorylation and nuclear translocation of a member of the STAT family (STAT3) of tran-
scription factors and finally elicit a cellular response (Turnbull and Rivier, 1999).
3. Hypothalamic-Pituitary-Adrenal Axis
The HPA axis is a feedback loop including the hypothalamus, pituitary and adrenal glands, regu-
latory neural inputs and a variety of releasing factors and hormones (Daban, 2005).
The primary CNS nucleus involved in the regulation of pituitary-adrenal axis is the
paraventricular nucleus (PVN) of the hypothalamus. The PVN is the principal CNS source of the
41-amino acid peptide CRH, which is the regulator of pituitary ACTH secretion (Rivier and
Plotsky, 1986).
The CRH from the paraventricular nucleus project to the median eminence and joined to
hypophysial portal vessels finally reach at the anterior pituitary. Within the anterior pituitary,
CRH interacts with specific G protein-coupled receptor (CRF-R1) on the corticotrope cell sur-
face, resulting in the stimulation of the synthesis of the ACTH precursor peptide
proopiomelanocortin (POMC) and the secretion of ACTH and other POMC-derived peptides
(Turnbull and Rivier, 1997).
Adrenocorticotropin hormone potently induces the secretion of GC from the zona fasciculata of
the adrenal cortex. In humans, the major GC is cortisol, but in the rat Corticosterone is the main
steroid product of the zona fasciculata. In a classical endocrine feedback manner, these steroids
inhibit the synthesis and secretion of CRF within the hypothalamus and POMC-derived peptides
4
Gp130 is a transmembrane protein which is the founding member of the class of all cytokine
receptors. It forms one sub unit of type 1cytokine receptors within the IL-6 receptor family.

in the pituitary (Keller and Dallman, 1984). Furthermore, the regulation of GC is subject to di-
verse sensory inputs and this information is integrated at the level of the hypothalamus. Small
deviations from normal circulating levels of these steroids produce changes in a wide variety of
physiological and biochemical parameters (Turnbull and Rivier, 1997).
Glucocorticoids act on multiple targets to enhance or inhibit various cellular activities, actions
that are aimed at providing the altered metabolic, endocrine, nervous, cardiovascular, and immu-
nologic needs that promote survival. In addition to secretions of glucocorticoids peak during
awakening time and nadir during the first few hours of sleep.
FIG.3 Functional Anatomy of Hypothalamic-Pituitary-Adrenal Axis (source: Turnball and Rivier, 1999)

4. Cytokines Effect on the Secretory Activities of HPA axis
As this mentioned in the introductory part of this review the bicommunication between the cen-
tral nervous system and immune system is very crucial to maintain homeostasis during threaten-
ing conditions.
The first demonstration of a possible link between the immune system and the hypothalamic-
pituitary-adrenal (HPA) axis came from the report that rats injected with sheep red blood cells
showed increases in plasma corticosterone levels that paralleled their immune response
(Besedovsky et al., 1975) This led to the proposal that activated immune cells released signals,
which stimulate the activity of the HPA axis. Thereafter numerous studies have confirmed and
extended the original findings that the administration of either IL-1α or IL-1β to rats or mice,
chickens (Wick et al.,1993), sheep (Vellucci et al.,1995), baboons (Reyes and Coe,1996 ) and
humans stimulates ACTH and GC secretion as well as many other indices of HPA.
In mammals, the ACTH response to intravenous IL-1 is usually prompt, commencing within 5–
10 min, and of relatively short duration (approximately 1hour). In comparison, the plasma ACTH
response to intraperitoneal injection of IL- 1β is slower in onset, but usually of longer duration
(at least 2h). Finally the response to IL-1 administered directly into the brain
(intracerebroventricularly) is of intermediate latency and lasts for several hours (>3-4 h). The
majority of studies have found IL-1β to be more potent than IL-1α in the rat (Matta et al., 1993,
Rivier et al., 1989).
A single administration of IL-1β not only acutely elevates plasma ACTH and corticosterone con-
centrations in the rat, but has been demonstrated to produce a long lasting (at least 3 wk) in-
crease in the co expression of AVP in hypothalamic CRF neurons and a hyperresponsiveness of
the HPA axis (Schmidt et al., 1995). Long-term administration of IL-1β to rats enhances CRF
and ACTH-like immunoreactivity in the hypothalamus and pituitary, respectively, increases Ad-
renal weight (Naito et al., 1989), and elevates plasma ACTH concentration for at least 7 days
(Van Der Meer et al., 1996).

In addition to the numerous studies of the effects of cytokines on the HPA axis of laboratory an-
imals, the clinical trials of a number of cytokines as anticancer strategies have afforded the op-
portunity to detail their effects on the HPA axis of humans. Such clinical studies have permitted
investigation of the effects of cytokines on the HPA axis in a homologous system (i.e. human
cytokines in human subjects). Either intravenous or subcutaneous administration of IL-1α (Curti
et al.,1996, Smith et al.,1992), IL-1β (Crown et al.,1991), IL-2 (Atkins et al.,1986, Denicoff et
al.,1989), IL-6, TNF-α and IFN-α (Gisslinger et al.,1993), IFN-β and IFN-γ elevates plasma
ACTH and/ or cortisol concentrations.
A series of experiments in which cancer patients of good clinical performances were examined
showed that IL-6 is a particularly potent activator of the HPA axis and that the human HPA axis
is remarkably responsive to this cytokine. On the first treatment day, IL- 6 (30 mg/kg sc) induced
marked elevations in plasma ACTH and cortisol concentrations, with peaks occurring at 1 and 2
hour respectively. Plasma ACTH concentrations returned to basal levels within 5 hours, whereas
plasma cortisol levels remained elevated for 24 h. By the seventh day of treatment, the ACTH
response to IL-6 was markedly diminished an effect that was probably due to increased negative
feedback produced by persistently elevated plasma cortisol levels. The sustained secretory activi-
ty of the adrenal gland was accompanied by gross enlargement of the adrenal glands as assessed
by computed tomographic scans (Mastorakos et al., 1993).
Overall, human and animal studies agree that many exogenously administered cytokines have
marked stimulatory actions on HPA axis secretory activity and suggest that endogenous produc-
tion of cytokines during homeostatic threats may well play a causal role in the elaboration of the
accompanying HPA axis response (Turnbull and Rivier, 1997).
5. Cytokine Actions on the Central Nervous System, Pituitary and Adrenal
The effects of both administrations of cytokines to normal, healthy subjects and the consequenc-
es of inhibiting cytokine action during infectious, inflammatory, or stressful threats imply that
cytokines may play a physiological role in the regulation of the secretory activity of the HPA ax-
is. However, cytokines also produce a number of systemic acute phase responses that themselves
could elicit HPA activation, here in we can raise the question of whether the effects of cytokines

on HPA axis secretory activity are direct or secondary to stress produced by other acute phase
responses. For example, IL-1β causes fever, sickness behavior, increases in heart rate, increased
blood flow to certain vascular beds, activation of the sympathetic nervous system, and changes in
intermediary metabolism. These physiological changes are themselves challenges to the mainte-
nance of homeostasis, and each could, if pronounced, activate secretion by the HPA axis (Turn-
bull and Rivier, 1999).
The effects of some cytokines on plasma ACTH concentrations have nevertheless been dissoci-
ated from a number of these other acute phase responses. For example, IL-1 induced activation
of the HPA axis of mice kept at an ambient temperature that did not result in these animals
mounting a febrile response (Besedovsky et al., 1986). Indeed, IL-1β analogs with markedly re-
duced pyrogenicity still stimulate ACTH secretion (Besedovsky et al., 1986). In addition, en-
hanced ACTH secretion is observed after peripheral administration of IL-1β at doses that have
no or only modest effects on the secretion of other hormones, such as luteinizing hormone,
catecholamines, and prolactin, whose secretion is markedly altered by many other types of
stressors (Rivier et al., 1989, Turnbull and Rivier, 1997). Similarly, doses of IL-6 that markedly
elevate plasma ACTH and cortisol concentrations in humans have only moderate effects on other
acute phase responses (Mastorakos et al., 1993).
The influence of IL-1 on pituitary ACTH secretion was attributable to actions either at the level
of hypothalamic CRF release or directly on the pituitary itself to stimulate ACTH secretion. Fur-
thermore, cytokines may act on the adrenal glands directly (Berkenbosch et al., 1987).
The following sections describe the evidence that indicates the potential site(s) of cytokine action
on HPA axis secretory activity
6. Evidence That Cytokines Activate the Hypothalamic-Pituitary-Adrenal Ax-
is Primarily at the Level of the Central Nervous System
6.1. Cytokine receptors within the CNS
Receptors of many cytokines have been localized within the CNS or described in primary cell
cultures or cell lines derived from brain tissue. These include receptors for IL-1, IL-2, IL-3, IL-4,
IL-6, IL-7, interferon, TNF, growth factor, CSF and neutrophins (Hopkins et al.,

1995).Regarding relevance to this review article is the distribution throughout the rodent CNS of
the receptors for the cytokines IL-1, IL-6, and TNF-α, and these are discussed in more detail
herein below.
6.1.1. IL-1 RECEPTORS IN THE CNS
Early studies investigating the localization of IL-1 receptors in the brain indicated fairly wide-
spread distribution (Turnbull and Rivier, 1999). High levels of specific binding of 125
I-labeled
IL-1β were found in the choroid plexus, dentate gyrus, hippocampus, cerebellum, and olfactory
bulb, with low levels in the hypothalamus of the rat brain slices (Farrar et al., 1987).
Specific binding of 125
I-labeled IL- 1β to membrane preparations of rat hypothalamus and cortex
were also reported (Katsuura et al., 1988). Subsequent studies have confirmed the existence of
IL-1 receptors within the rodent CNS, and IL-1R1 mRNA or IL-1 binding have been demon-
strated on neurons, astrocytes (Ban et al., 1993), cerebrovascular endothelia (Van Der Meer et
al., 1996), neuroblastoma cells (Parnet et al., 1994) and glioblastoma cells, but not on microglia
(Ban et al., 1993). However, the localization within the rat brain appears to differ somewhat
from that which was originally reported, in particular with respect to the presence of IL-1 recep-
tors within the hypothalamus. Furthermore, there are marked differences in the distribution of
IL-1 receptors in rat and mouse brains (Turbull and Rivier, 1999).
Overall, the mouse brain exhibits very low densities of IL-1 receptors as assessed by binding of
125
I-labeled IL-1α, IL-1β, or IL-1ra. However, very high levels of labeling are found consistently
in the hippocampus (dentate gyrus, but not CA1 to CA4 pyramidal regions), choroid plexus, and
meninges. Within the dentate gyrus, IL-1 binding appears to be predominantly to neurons. In situ
hybridization histochemical analyses of mouse brains have indicated that IL-1R1 mRNA is ex-
pressed predominantly in the granule cell layer of the dentate gyrus, the entire midline raphe sys-
tem, the choroid plexus, and endothelial cells, but not in the hypothalamus. In contrast, IL-1R2
mRNA has been undetectable in normal mouse brain using in situ hybridization histochemical
procedures (Cunningham et al., 1991).

Analysis using PCR5
and immunocytochemistry techniques demonstrated unequivocally that the
human hypothalamus express both messenger RNA and protein of the IL-1R1 (Hammond. et al.,
1999).
6.1.2. IL-6 RECEPTORS IN THE CNS
Specific IL-6 binding sites binding have been demonstrated in both astrocytoma and
glioblastoma cell lines as well as in extracts of bovine hypothalamus (Cornfield and Sills, 1991).
Messenger RNA encoding α subunit of the IL-6 receptor (IL-6Rα) has been detected in neurons,
microglia, and astrocytes from normal brain tissue, primary cell cultures, or tumor cell lines. Fur-
thermore IL-6Rα mRNA is expressed in several brain regions of the untreated rat and mostly
abundant in the pyramidal cells of the CA1 and CA4 regions of the hippocampus and the granule
cell layer of the dentate gyrus and has also been detected in the hypothalamus, cerebellum, hip-
pocampus, striatum, neocortex, and pons/medulla (Schobitz et al., 1992, Vallieres and Rivest,
1997).
Specific hybridization signals are observed in glial cells of the lateral olfactory tract, in ependy-
mal cells of the olfactory and anterior lateral ventricle and in neurons of the piriform cortex, me-
dial habenular nucleus, neocortex, hippocampus, and hypothalamus. Within the hypothalamus,
IL-6Rα mRNA is present in the ventromedial and dorsomedial regions including the periventric-
ular hypothalamus and in the medial preoptic nucleus. However, the anterior hypothalamus and
PVN display no specific hybridization signal for IL-6Rα mRNA (Schobitz et al., 1992).
The expression of IL-6Rα mRNA in the rat brain appears to be developmentally regulated, with
marked increases in its expression, particularly in the striatum, hypothalamus, hippocampus, and
neocortex, between 2 and 20 days of age. Furthermore, LPS administration markedly elevates
IL-6Rα mRNA levels in several rats within the brain regions (area postrema, bed nucleus of the
5
A technique used to replicate a fragment of DNA and produce a large amount of that sequence

stria terminalis, amygdala, cerebral cortex, claustrum, hippocampus, ME, piriform cortex,
septohippocampal nucleus, PVN, SFO, and OVLT) and over the blood vessels throughout the
brain (Vallieres and Rivest, 1997).
gp130, the signal transducing component of the IL-6 receptor, has also been localized within the
rat brain, expressed in glial, neuronal, Oligodendrocytes, and ependymal cell types (Vallieres and
Rivest, 1997). Furthermore, it has been detected by positive hybridization6
signals in the normal
rat brain and almost detectable in all brain areas includes the hypothalamus and, of particular in-
terest, the PVN (Vallieres and Rivest, 1997).The distribution of immunoreactive gp130 in the rat
brain overlaps that which has been observed for IL-6Rα but is more widespread, consistent with
its role in signal transduction for other members of the IL-6 family (Watanabe et al., 1996).
6.1.3 TNF Receptors in the CNS
In vitro studies have shown that both, TNF-R1 and TNF-R2 mRNA are present in mouse cere-
brovascular endothelium. Furthermore in microglia, astrocytes, and oligodendrocytes, has been
expressed in humans (Wilt et al., 1995), whereas at least one receptor subtype is present in rats
and mice (Dopp et al., 1997). Both undifferentiated and differentiated clonal murine
neuroblastoma cells (N1E cells) express TNF-R1, but not TNF-R2, mRNA (Sipe et al., 1996).
The TNF-R1 immunoreactivity has also been demonstrated in neurons in the substantia nigra of
humans and both TNF-R1 and TNF-R2 immunoreactivities shown in human hippocampal and
striatal neurons. However, there is no evidence that either TNF-a receptor subtype is localized to
hypothalamic regions directly involved in the regulation of HPA axis secretory activity (Turnbull
and Rivier, 1999).
6
In situ hybridization is a technique that uses a labelled complementary RNA strand (i.e. probe)
to localize a specific mRNA sequence in a section of tissue.

6.2. Cytokine expression in the CNS
6.2.1. Basal expression
Many cytokines are synthesized within the brain, although in most cases their expression in
healthy, stress-free subjects is low. Nonetheless, a number of studies have reported the distribu-
tions of IL-1, IL-6, and TNFα immunoreactive or biologically active protein or mRNA in the
brains from normal untreated subjects (Turnbull and Rivier, 1999).
In the human brain, IL-1β immunoreactivity is found within neuronal elements of the hypothal-
amus, including periventricular regions, the PVN, and the median eminence. This distribution is
consistent with a role of IL-1β as a neuroregulator of acute phase responses, and in particular, of
the HPA axis. Although studies in rats also detected neuronal immunoreactive IL-1β in similar
hypothalamic regions, more prominent staining was found in extrahypothalamic sites, particular-
ly the hippocampus (Lechan et al., 1990, Rettori et al., 1994).
In the normal rat or mouse hypothalamus, IL-1β is detectable using sensitive immuno assays
7
(Hagan et al., 1993).However, the majority of in situ hybridization studies have found that the
brain parenchyma lacks a readily distinguishable IL-1β mRNA signal (Higgins and Olschowka,
1991, Minami et al., 1991), whereas constitutive expression of IL-1β in the cerebrovasculature of
control animals is readily observable. Similarly, the majority of Northern blot hybridization8
or
RT- PCR studies have found extremely low or undetectable levels of IL-1α or IL-1β mRNA in
the brains of control rats or mice (Gatti and Bartfai, 1993, Higgins and Olschowka, 1991, Laye et
al., 1994), although sufficient sensitivity to demonstrate small diurnal variations in rat brain IL-
1β mRNA expression was achieved in one study (Taishi et al., 1997).
7
A specific type of biochemical tests that measure the presence or concentration of a substance
in solutions that frequently contain a complex mixture of substances.
8
A technique used to study gene expression by detection of RNA (isolated RNA)

Messenger RNA of the gene encoding ICE9
has been demonstrated in murine microglia (Yao and
Johnson, 1997), whole brain homogenates (Keane et al., 1995), homogenates hippocampus
(Laye et al., 1996), and blood vessels (arterioles and venules) throughout the brain parenchyma
of control rats.
Interleukin-1 receptor antagonist mRNA is also present within the rat brain (Gayle et al., 1997,
Ilyin et al., 1996, Licinio et al., 1991), with positive in situ hybridization signal present in the
hypothalamus (particularly the PVN), hippocampus, cerebellum, choroid plexus, and blood ves-
sels throughout the brain (Licinio et al., 1991).
Tumor necrosis factor α immunoreactivity is found in the hypothalamus, caudal raphe nuclei,
and along the ventral surface of the brain in the normal mouse brain (Breder et al., 1993). On the
basis of morphological observations, the majority of staining observed appears neuronal, with
two principal fiber pathways being noted: A periventricular pathway which coursed along the
ventricular system and a pathway associated with the medial forebrain bundle (Breder et al.,
1993). Within the hypothalamus, the PVN represents one of the terminal fields of fibers originat-
ing from the most intensely stained cell groups within the bed nucleus of the stria terminalis. On
the basis of in situ hybridization studies, there is only a weak signal over regions that coincided
with immunoreactive TNF-α (Breder et al., 1993). Finally, IL-6 mRNA has been either undetect-
able (Vallieres and Rivest, 1997 ) or shown to be colocalized with IL6Rα mRNA within several
regions of the normal rat brain, including hypothalamus, cerebellum, hippocampus, striatum,
neocortex, and pons/ medulla ( Schobitz et al., 1993).
6.2.2 Induced Expression
The expression of a number of cytokines within the CNS increases dramatically up on cellular
damage. Accordingly, local concentrations of IL-1β, IL-6, and TNF-α, in particular, are elevated
during CNS bacterial or viral infections, brain trauma, cerebral ischemia, and convulsions. In
addition, their expression is increased during a number of chronic CNS disorders such as multi-
ple sclerosis, Down’s syndrome, and Alzheimer’s disease (Hopkins and Rothwell, 1995). In gen-
eral, when induction of cytokine synthesis within the brain has been demonstrated, microglia ap-
pear to be the major brain cell type that synthesizes ILs, chemokines, TNF and IFN, although
9
An enzyme responsible for cleavage of pro-IL-1β to mature, active IL-1β.

vascular cells, astrocytes, and neurons also contribute to cytokine production (Turnbull and
Rivier, 1999).
The synthesis of cytokines in brain may be induced by stimuli other than those resulting in di-
rect cellular challenge to the CNS, and consequently that cytokines may act as neuroregulators
within the brain in a manner to classical neuropeptides. Indeed, in response to the peripheral ad-
ministration of LPS10
, the CNS expression of a number of cytokines is elevated. In response to
large doses of LPS (0.4–4 mg/kg Ip or IV), the mRNA encoding IL-1α, IL-1β, IL-1rα, IL-6, and
TNF-α are elevated in homogenates of several regions of the mouse brain as assessed by RT-
PCR and Northern blot hybridization methodologies (Gabelle et al., 1995, Gatti and Bartfai,
1993,Muramami et al., 1993). These elevations have been noted within 1h, and peak at approxi-
mate 6 h. However, an important question regarding the induction of cytokines in the brain by
LPS is whether the stimulus causing increased synthesis is of peripheral origin, because large
doses of LPS could, for example, penetrate the BBB in sufficient quantities to stimulate cytokine
synthesis directly. Indeed, LPS is a potent stimulus of IL-1, IL-6, and TNF-α synthesis after its
intracerebroventricular administration (De simoni et al., 1995, Higgins and Olschowka, 1991)
and induces cytokine synthesis by glial cells in cell culture (Sharif et al., 1993). In addition, large
doses of LPS may disrupt the BBB (Boje, 1995, Liu et al., 1996, Lustig et al., 1992, Tunkel et
al., 1991, Shukla et al., 1995), thus permitting the entrance from the periphery of cells (e.g.,
macrophages) that may contribute to the cytokine signal.
Recent studies have suggested that cytokine synthesis in brain may also be induced by stressors
unrelated to infection or inflammation. Hypothalamic expression of IL-1β mRNA (Minami et al.,
1991, Suzuki et al., 1997), IL-1rα mRNA (Suzuki et al., 1997), and IL-1 bioactivity (Shintani et
al., 1995) is increased within 30 min of immobilization stress in the rat, and IL-6mRNA is ele-
vated in the mid brain 4–24 h after restraint stress (Shizuya et al., 1997). Similar paradigms pro-
duce increases in IFN-γ mRNA expression in mouse brain homogenates (Take et al., 1996).
Acute (2 h) or repeated immobilizalation stress in rats increases BDNF mRNA expression in the
10
Lipopolysaccharide is the bacterial cell wall product endotoxin

pPVN and the lateral hypothalamus and decreases BDNF mRNA in the hippocampus, whereas
repeated stress increases NT-3, but not NT-4, mRNA in the hippocampus (Smith et al., 1995).
6.3. Cytokine actions at the level of the CNS
Consistent with the CNS as a primary target of IL-1 action in eliciting pituitary ACTH secretion,
administration either IL-1α or IL-1β directly into the cerebroventricles (intracerebroventricular)
of rats markedly elevates plasma ACTH concentrations. Elevation in plasma ACTH concentra-
tions produced by intracerebroventricular IL-1generally occurs at considerably lower (5- to 20-
fold less) doses than those required by intravenous IL-1 (Katsuura et al., 1988, Rivest et al.,
1992, Vander Meer et al., 1996). Similarly, IL-2, IL-6, TNF-α, and epidermal growth factor
(EGF) have been shown to elevate plasma ACTH and/or corticosterone concentrations when
administered via the intracerebroventricular route. Interleukin-1 infused directly into several
brain sites, including the PVN (Barbanel et al., 1990, Watanobe and Takebe, 1993), median emi-
nence (Matta et al., 1990), and hippocampus (Linthorst et al., 1994), also increases pituitary
ACTH secretion.
The effectiveness of cytokines when administered directly into the brain, and in particular the
fact that lower doses are usually required to stimulate HPA axis secretory activity than when
administered peripherally, have been interpreted as evidence that the activation of the HPA axis
by peripherally administered cytokines occurs via an action within the CNS. This assumption is
based on dose-response studies and with patterns of gene expression of IL-1β and TNFα, within
the PVN (Lee and Rivier, 1994, Rivest et al., 1992, Rivier, 1995).
A number of lines of evidence do suggest that the stimulation of pituitary ACTH and adrenal GC
secretion by either centrally or peripherally administered cytokine is due to an action at or above
the level of the hypothalamus. Indeed, surgical lesioning studies indicate the importance of an
intact hypothalamus to the elaboration of a plasma ACTH response to IL-1β in the rat. Electro-
lytic obliteration of the rat PVN also markedly reduces the rise in plasma ACTH concentrations
produced by a number of cytokines, with inhibition being complete in the cases of
intracerebroventricular IL-1β (Rivest and Rivier, 1991) or intravenous IL-6, approximately70%

after intravenous TNF-α, and 50% when IL-1β is injected intravenously (Kovacs and Elenkov,
1995).
Strong evidence that IL-1 stimulates the secretory activity of the HPA axis primarily by an action
on the CNS comes from studies that have demonstrated that IL-1 rapidly stimulates the secretion
of CRH from the ME into hypophysial portal blood vessels. Corticotropin-releasing hormone is
depleted from the ME of colchicine-treated rats within 1 h of intraperitoneal IL-1β (Berkenbosch
et al., 1987), and CRH concentrations in portal blood are elevated within 30 min of intravenous
IL-1β (Sapolsky et al., 1987). In the perfusates from push-pull cannulas placed within the ME,
CRH concentrations are elevated within 5 min of either intracerebroventricular or intra-PVN
IL-1β (Barbanel et al., 1990) and precede the rise in plasma ACTH after intravenous IL-1β
(Watanobe et al., 1991, Watanobe and Takebe, 1994). Similarly, intravenous TNF-α produces an
immediate rise in CRH secretion (Watanobe and Takebe, 1992). Histological examination of
hypophysiotropic nerve terminals suggests that AVP may (Whitnall et al., 1992) or may not
(Berkenbosch et al.,1989) be cosecreted with CRH in response to peripheral IL-1, whereas elec-
trophysiological data indicate that increased activity in the PVN is selective for neurons contain-
ing CRH only (Saphierd and Ovadia, 1990).
Despite the fact that no IL-1 receptors have been demonstrated in the PVN, a number of studies
demonstrate that IL-1 stimulates the secretion of CRH from the hypothalamus in vitro. Incuba-
tion with subnanomolar doses of IL-1α or IL-1β has consistently been reported to rapidly (within
minutes) increase the release of CRH from rat hypothalamic explants, superfused hypothalamic
tissue, as well as dispersed hypothalamic cell cultures. In addition, IL-1β increases the CRF con-
tent of hypothalamic explants, indicating an increase in CRH peptide production (Hagan et al.,
1993).
Collectively, the rapid effects of IL-1 and other cytokines on hypothalamic CRH secretion in vi-
vo and in vitro, together with the reduction of plasma ACTH responses to cytokines produced by
inhibiting the actions of CRH, provide an extremely strong case for the CNS as a primary site of
cytokine action in the stimulation of HPA axis secretory activity. Nevertheless, a large number of
in vitro studies have also indicated the possibility of direct effects of cytokines on pituitary
ACTH secretion and adrenal GC secretion (Turnbull and Rivier, 1999).

7. Evidence for Direct Effects of Cytokines on Pituitary Adrenocorticotropic
Hormone Secretion
7.1. Cytokine receptors within the pituitary
A number of cytokine receptors have been localized in the pituitary. For example, 125
I-labeled
human IL-1α (Ban et al., 1993, Cunningham et al. 1991, Takao et al., 1992), IL-1β or IL-ra (Ta-
kao et al., 1992), or rat IL-1β (Marquetee et al., 1995) bind specifically to the anterior lobe of the
mouse pituitary gland, with little or no IL-1 binding apparent in the mouse posterior pituitary
(Ban et al., 1993, Marquetee et al., 1995). Pituitary IL-1 binding in the mouse is decreased by
systemic treatment with LPS and increased by immobilization stress, ether-laparotomy stress,
and long-term treatment (7 day) with GC (Ban et al., 1993).
RT-PCR experiments have demonstrated the presence of both IL-1R1 and IL-1R2mRNA in the
whole mouse pituitary (Parnet et al., 1993 ).Insitu hybridization histochemistry experiments
agree with IL-1binding studies and show that IL-1R1 mRNA is present in the mouse anterior, but
not posterior pituitary. Interleukin-1 binding and IL-1R1 and IL-1R2 mRNA have also been
demonstrated in the mouse corticotropic tumor cell line AtT20 (Bristulf and Bartfai, 1995, Ko-
bayashi et al., 1992, Tracey and De souza, 1988).
Interestingly, and in accordance with the stress-induced increases in IL-1 binding in the anterior
pituitary of the mouse, CRF increases IL-1α binding in AtT20 cells, while IL-1β and TNF-α in-
creases the expression of both IL-1R1 and IL-1R2 mRNA (Bristulf and Bartfai, 1995). However,
the expression of IL-1R1 and IL-1R2 by AtT20 cells does not necessarily indicate that normal
corticotropes contain cell-surface IL-1 receptors. Indeed, when IL-1R1 and IL-1R2
immunoreactivities were localized to particular endocrine cell types in the normal mouse anterior
pituitary, no evidence of colocalization of IL-1 receptor with ACTH was apparent (French et al.,
1996). Much less work has focused on the presence of IL-6 and TNF-α receptors within the pi-
tuitary. Rodent anterior pituitaries exhibit binding of 125
I-labeled IL-6 (Ohmichi et al., 1992) and
IL- 6Rα mRNA is expressed in normal rat (Velkeniers et al., 1994) and fetal and adult human
pituitaries (Shimon et al., 1997).

Interleukin-6Rα is also expressed in human ACTH and growth-hormone secreting tumors (Rezai
et al., 1994, Velkeniers et al., 1994). In addition, the IL-6R signaling subunit gp130 is present in
human fetal pituitary cells (Shimon et al., 1997). High concentrations of binding sites form TNF-
α have also been demonstrated in the mouse and rat anterior pituitaries (Wolvers et al., 1993),
AtT20cells and the folliculostelate cell line TtT/GF.
7.2. Cytokine expression in the pituitary
The pituitary has been shown to produce a diverse range of cytokines. Some of these cytokines
(e.g., IL-2, IL-10, LIF, and MIF) have been localized to corticotropes or demonstrated in the
corticotrope cell line AtT20 (Arzt et al., 1992, Bucala, 1994).
In vivo mRNA encoding the cytokines IL-1α, IL-1β, IL-6, LIF, IFN-γ, and TNF-α mRNA in the
pituitary are all elevated by 45 min to 6 h after treatment with LPS (Laye et al., 1994, Muramami
et al, 1993, Tingsborg et al., 1996). Anterior pituitary IL-6 mRNA is also increased by chronic,
local inflammation (Sarlis et al., 1993). The constitutive expression of IL-1ra in the pituitary
(Gabellec et al., 1995, Gatti and Bartfai, 1993, Licinio et al., 1991) is of particular interest given
its ability to antagonize the effects of IL-1 agonists, suggesting that the responsiveness of the pi-
tuitary to IL-1 may be modulated at a local level. Interleukin-1ra mRNA has been reported to be
either unaffected (Gatti and Bartfai, 1993) or induced (Gabellec et al., 1995, Licinio et al., 1991)
by systemic treatment with LPS.
The regulation of IL-6 secretion from anterior pituitary cell cultures has been investigated exten-
sively. Anterior pituitary cells constitutively produce IL-6 and the secretion of this cytokine can
be induced within 6hours treatment with LPS, IL-1a, IL-1b, TNF-α, the IFN family,
phorbolmyrisate and agents that elevate cAMP (Spangelo et al., 1991).
Accordingly, dibutyryl cAMP, prostaglandin E2, forskolin, and cholera toxin all increase IL-6
secretion from rat anterior pituitary cell cultures (Spangelo et al., 1991, Carmeliet et al., 1991).
Some (VIP, pituitary adenylate cyclase activating peptide (PACAP), and calcitonin gene-related
peptide) but not all (CRF, growth hormone releasing factor) neuropeptides that utilize cAMP-
coupled receptors for signaling, therefore, also stimulate IL-6 secretion in anterior pituitary cells.
However, the induction of IL-6 secretion from anterior pituitary cells by IL-1b does not appear to

be mediated by cAMP-dependent pathways, since in these cells, no increase in intracellular
cAMP is apparent after treatment with IL-1β (Spangelo and Gorospe, 1995).
Glucocorticoids inhibit basal and IL-1β stistimulated (Carmeliet et al., 1991, Spangelo et al.,
1991) IL-6 release from rat anterior pituitaries. In addition to secretion from anterior pituitary
cells, IL-6 is released by neurointermediate lobe cells in culture, with IL-1β and LPS again being
potent secretagogues. The cell source within the normal anterior pituitary does not appear to be a
classical endocrine cell type. Rather, folliculo stellate11
(FS) cells are the major sources of IL-6
FS-like cell line has been isolated (TtT/GF) and constitutively secrete IL-6, and IL-6 secretion is
enhanced by TNF-α, VIP, PACAP) and IL-1β (Kobayashi et al., 1992).
7.3. Direct effects of cytokines on pituitary ACTH
In vitro studies indicating that with the exception of activin, which inhibits POMC mRNA ex-
pression and ACTH secretion in the corticotropic tumor cell line AtT20 and reduces ACTH se-
cretion from primary cultures of rat anterior pituitary cells all other cytokines studied have been
reported to either enhance or have no effect on either ACTH secretion or POMC mRNA expres-
sion in otherwise untreated pituitary cells (Bilezikjian et al., 1991).
IL-1β, IFN-γ, and GM CSF stimulate ACTH secretion from cultured human pituitary adenoma
cells from patients with Cushing’s disease (Malarkey and Zvara, 1989). The duration of exposure
of AtT20 cells and human pituitary adenoma cells to cytokines required to elicit statistically sig-
nificant increases in ACTH secretion has, in general, been long. Although one report indicates
increases in ACTH produced by either IL-1 or IL-6 within 2h (Woloski et al.,1985), the majority
have used incubation times ranging from 6 to 72 h (Akita et al.,1995 ,Brown et al., 1987 , Ray et
al., 1996, Stefana et al., 1996 ). The fact that many cytokines have a stimulatory effect on pitui-
tary tumor cells indicates the ability of signal transduction path ways activated by cytokine-
cytokine receptor interaction to influence POMC expression and/or ACTH secretion. However, it
is unclear to what extent corticotrope tumors accurately represent normal anterior pituitary
corticotropes.
11
Folliculostelate cells are of monocytic lineage and are thought to be involved in paracrine regula
tion of hormone secretion from the pituitary

For example, although AtT20 cells possess both IL-1R1 and IL-1R2 mRNA (Bristulf and
Bartfai, 1995, De souza et al., 1989, Tracey and De Souza, 1988), immuno staining of normal
mouse pituitary does not show significant IL-1 receptor expression by corticotropes (French et
al., 1996).
8. Evidence for Direct Actions of Cytokines on Adrenal Glucocorticoids Secre-
tion
The adrenal gland displays no positive in situ hybridization signal for IL-1R1 mRNA, whereas
IL-6Rα mRNA has been detected mainly in the zona glomerulosa and fasciculata in human ad-
renals (Path and Bornstein, 1997) and also in the adrenal medulla (Gadient et al., 1995).
8.1. Cytokine expression in the adrenal gland
In the adrenal gland, large constitutive pools of IL- 1α and IL-1β have been identified. Interleu-
kin-1α, IL-1β, and IL-1ra immunoreactivities have been demonstrated in adrenal chromaffin
cells (Bartfai et al., 1990). In addition, IL-1α, IL-1β, ICE, and IL-1ra mRNA are present in the
adrenal cortex and are markedly elevated in both adrenal medulla and cortex 90 min after intra-
venous or intraperitoneal LPS (Schultzberg et al., 1995, Tingsborg et al., 1997).
Interestingly, the IL-1-related cytokine IL-18/IL-1γ is also synthesized within the rat adrenal cor-
tex, mainly in the zona reticularis and fasciculata, and is strongly induced by acute cold stress
(Conti et al., 1997). Interleukin-6 mRNA is also present throughout the human adrenal cortex
(Gonzalez et al., 1994, Path and Bornstein, 1997), and rat adrenal gland extracts contain IL-6
mRNA (Gadient et al., 1995, Muramami et al., 1993, Schobitz et al., 1993), which is markedly
induced 2hours after intraperitoneal LPS (Muramami et al., 1993). Although TNF-α mRNA has
been described throughout the cortex of human adult adrenals, particularly in steroid-producing
cells, TNF-α immunoreactive protein has been detected in only 12 of 22 fetal, and in 0 of 7 adult,
human adrenals (Jaattela et al., 1990).
A number of growth factors are also present in the adrenal: basic fibroblast growth factor mRNA
or protein is present in whole human adrenals, in rat, bovine cortex or medulla, TGF-β1 mRNA

and protein in bovine adrenal cortex and mouse whole adrenal and NT-3 protein has been report-
ed in whole rat adrenal (Basile and Holzwarth., 1993, Grothe and Unsicker, 1990).
Studies of primary cultures of dispersed adult rat adrenal glands have indicated the likely cellular
sources and major secretagogues of the cytokines IL-6 and TNF-α within the adrenal gland. Alt-
hough the zona fasciculata/reticularis produce small amounts of TNF-α and IL-6, the primary
source of IL-6 in the rat adrenal is the zona glomerulosa. The secretion of TNF-α and IL-6 from
adrenal glomerulosa cells is stimulated in a dose-dependent manner by LPS, IL-1α, and IL-1β.
Furthermore, IL-6 secretion from these cells is enhanced by protein kinase C activators, the cal-
cium ionophore ionomycin, prostaglandin E2, forskolin, and angiotensin II (Judd and Macleod,
1995). Unlike most cell types that produce IL-6, dexamethasone does not influence either basal
or IL-1b-stimulated IL-6 secretion in zona glomerulosa cells (Judd and Macleod, 1992). Interest-
ingly, ACTH increases the release of IL-6 from zona glomerulosa cells but not zona
fasciculata/reticularis, despite similar ACTH-stimulated cAMP levels in each cell type (Judd and
Macleod, 1992). Such ACTH-induced IL-6 release from the adrenal suggests that activation of
the HPA axis per se may cause IL-6 secretion from the adrenal. Like IL-6, TNF-α secretion is
stimulated by protein kinase C activators and ionomycin. However, in stark contrast to IL-6, ba-
sal and stimulated TNF-α release is dose dependently inhibited by ACTH and dibutyryl cAMP
(Judd and Macleod, 1995). Similarly, differentia effects on IL-6 and TNF-α secretion from zona
glomerulosa cells are observed with serotonin and adenosine (Ritchie et al., 1996).
8.2. Direct effects of cytokines on adrenal glucocorticoids secretion
Despite a lack of evidence for the presence of IL-1, IL-6, or TNF-α receptors within the adrenal
gland, direct actions of these cytokines on GC secretion have been demonstrated. In vivo, pe-
ripheral administration of IL-1β has been reported to either stimulate or exert no effect on
corticosterone secretion in hypophysectomized rats and to induce secretion of GC in anesthetized
rats with isolated adrenal glands (Roh et al., 1987). The doses required to observe direct effects
of IL-1β on adrenal corticosterone secretion in vivo have, however, been extremely high, which
is 35 μg /rat and casts doubt on the physiological relevance of this effect (Gwosdow et al., 1990).

In vitro studies have indicated that IL-1β does not influence either basal or ACTH-stimulated GC
production from human fetal adrenal tissue either in cell or organ culture (Harlin and Parker,
1991). However, either IL-1α or IL-1β increases GC secretion from rat quartered adrenals, rat
adrenal slices, or rat, bovine and human dispersed adrenal cells (Mazzocchi et al., 1993,
O’Connell et al., 1994, Tominaga et al., 1991, Winter et al., 1990). Similarly, IL-2, IL-3, and IL-
6 induce GC secretion from various adrenal cell preparations (Darling et al., 1989, Tominaga et
al., 1991), and IL-6 potentiates corticosterone secretion induced by low concentrations of ACTH
(Salas et al., 1990).
Tumor necrosis factor-α stimulates cortisol secretion from adult adrenocortical cells (Darling et
al., 1989) but inhibits ACTH-induced cortisol secretion from human fetal adrenal tissue and cul-
tured cells (Jaattela et al., 1991). Interferon-γ stimulates corticosterone secretion from primary
dispersed rat adrenal cells (Gisslinger et al., 1993) and normal human adrenal slices (Cardoso et
al., 1990), whereas NGF does not influence either basal or ACTH-stimulated corticosterone pro-
duction from dispersed rat adrenal cell cultures (Scaccianoce et al., 1993).
Finally, these in vitro studies provide strong evidence that some cytokines may influence GC se-
cretion directly. However those studies required incubations in excess of 12h to observe signifi-
cant effects of cytokines on GC secretion.
9. Mechanisms OF Hypothalamic Pituitary Adrenal Axis Activation by Inter-
leukin-1
The distributions of various cytokines and their receptors throughout the brain, pituitary, and to a
lesser extent in the adrenal provide an anatomic basis for the hypothesis that cytokines influence
the function of these organs.
Elucidating the mechanisms by which particular cytokines may activate the HPA axis during a
particular threat to homeostasis has focused on the cytokine IL-1 and to a much lesser extent IL-
6 and TNFα.

Almost all proinflammatory cytokines stimulate the HPA axis in vivo (Turnbull and Rivier,
1999) and proopiomelanocortin (POMC) expression in vitro (Katahira et al., 1998). HPA stimu-
lation occurs either at the hypothalamic level (IL-1β, TNFα), inducing CRH gene expression and
CRH release. In addition to CRH, inflammatory cytokines also trigger central ACTH
secretagogues such as noradrenaline (Giovambattista et al., 2000), pituitary adenylate cyclase-
activating polypeptide (PACAP), vasopressin, and other cytokines. Furthermore stimulation of
HPA axis also occurs at the level of pituitary corticotrophs. IL-2, interferons, and the gp130 cy-
tokine family participate in ACTH regulation and mediate the immuno neuroendocrine interface
9.1. Direct Actions of IL-1 on Pituitary and Adrenal
IL-1 may be capable of having direct actions on the pituitary to enhance the secretion of ACTH
and on the adrenal cortex to increase GC secretion. Receptors for IL-1 are clearly present in the
anterior pituitary, although it is unlikely that these are expressed on normal corticotropes. The
pituitary and adrenals clearly would be exposed to IL-1 if its concentrations in blood were ele-
vated (e.g., severe endotoxemia). In addition, IL-1 can be synthesized locally within these tis-
sues. However, it seems clear that prolonged exposure of the pituitary or adrenals to IL-1 is nec-
essary to elicit the release of ACTH or GC, respectively. Therefore, direct actions of IL-1 on ei-
ther the pituitary or adrenal do not appear to account for a significant component of the hormone
secretion observed in response to acute exposure to IL-1 in vivo.
Circumstances involving prolonged increases in cytokines, for example, during chronic inflam-
mation (Sarlis et al., 1993,), may well involve direct actions of IL-1 or other cytokines on the
pituitary ACTH and/or adrenal GC secretion. Furthermore, enhanced pituitary or adrenal synthe-
sis of IL-1 may regulate these glands’ growth and development (Arzt and Stalla et al., 1996,
Renner et al., 1995, Zieleniewski and Stepien, 1995). Similarly, a number of other interleukins
(e.g., IL-2, IL-6) and growth factors (e.g., EGF) have been shown to influence the growth of the
pituitary or adrenal glands (Arzt and Stalla et al., 1996, Pereda et al., 1996).
A large body of evidence indicates that the level of the HPA axis primarily affected by IL-1 is
the hypothalamus. This is true whether IL-1 has been administered directly into the brain or into

the periphery. This raises the question of how a blood-borne, large, hydrophilic peptide such as
IL-1 accesses the CNS to influence hypothalamic secretions.
To address for the above raised question different possible mechanisms have been proposed.
These mechanisms includes blood-borne cytokine acting at a Circumventricular organ (CVO), at
vagal or other afferent nerves, altering the permeability of the BBB to other substances, disrupt-
ing the BBB, enhancing or inducing the passage of immune cells from blood to brain, and affect-
ing the release of another substance which in turn crosses the BBB or acts through one of these
mechanisms. Herein, Attempts has been made to clarify only some of the proposed mechanisms
related to the topic of this paper.
9.2. Penetration of Cytokines into Brain
The transport of solutes out of vascular compartments and into perivascular tissue (or vice versa)
occurs via either paracellular or transcellular mechanisms. Within the cerebrovaculature, the
paracellular route is particularly impermeable due to the presence of the BBB12
. The paracellular
Ultrafiltration of solutes into and out of tissues that occurs in peripheral vascular beds does there-
fore not occur in most cerebrovascular beds, at least while the BBB remains intact. Furthermore,
the large molecular size (8– 65 kDa) and hydrophilic nature of cytokines preclude their move-
ment transcellularly by simple diffusion to any appreciable extent. Indeed, early studies conclud-
ed that the BBB was impermeable to IL-1 (Blatteis, 1990, Coceani et al., 1988). However,
transport of cytokines via the paracellular route can occur (Banks et al., 1994), when BBB integ-
rity is compromised, and saturable transcellular transport mechanisms for a number of cytokines
have now been described.
12
BBB consists primarily of nonfenestrated endothelial cells that are connected by tight junc-
tions and thus form a continuous cell layer that has the permeability properties of a continuous
plasma membrane.

FIG.4 Proposed Models by Which Lnterleukin-1 Influences Secretory Activity of Hypothalamic
Pituitary-Adrenal Axis (Source: Turnball and Rivier, 1999)
9.3. Cytokines and Blood-Brain Barrier Integrity
Loss of BBB integrity may occur during inflammatory insults to the brain such as those accom-
panying CNS disease (e.g., multiple sclerosis, meningitis, brain tumors, and AIDS dementia),
brain trauma, cerebrovascular lesions, or seizures (Johansson, 1995). Furthermore, administra

tion of large doses of LPS increases BBB permeability (Boje, 1995, De Vries et al., 1996, Liu et
al., 1996, Lustig et al., 1992, Tunkel et al., 1991). Such disruption of the BBB enables not only
the passage of large peptides such as cytokines, but also augments the rate of entry of cells, such
as macrophages, monocytes, lymphocytes, and neutrophils, which are capable of cytokine syn-
thesis and secretion, but whose passage into the normal healthy brain is very limited.
The association between peripheral inflammatory events and the CNS production of cytokines
has led to a number of studies investigating the possible influence of cytokines on BBB permea-
bility. In monolayer cultures of cerebral endothelial cells, LPS or IL-1β, IL-6 or TNFα produces
a decline in transendothelial electrical resistance data supportive of an elevation in BBB permea-
bility (DeVries et al., 1996). In vivo studies have demonstrated that intracerebroventricular TNF-
increases BBB permeability in the rat (Kim et al., 1992) and pig (Megyeri et al., 1992), and en-
hanced brain TNF-α producation has been linked to the increased BBB permeability associated
with a number of CNS inflammatory conditions (Sharief et al., 1992, Shohami et al., 1996).
Enhanced BBB permeability as a result of either CNS or severe peripheral infection may there-
fore permit the entry of cytokines themselves or cytokine-producing cells into the CNS, and cy-
tokines so derived may contribute to CNS-mediated acute phase responses. However, it is clear
that the initial neuroendocrine effects of peripheral administered cytokines or LPS can be ob-
served more quickly, and at lower doses, than can be accounted for by damage to the BBB
9.4. Carrier-mediated transport of cytokines across the blood-brain barrier
Transcellular, saturable transport mechanisms afford a means of cytokine entry into the brain,
even when BBB integrity is not compromised (Banks et al., 1995). These include saturable
transport mechanisms for IL-1 α, IL-1β, IL-6, IL-1ra and TNF-α but not IL-2 (Gutierrez et al.,
1994).
The members of the IL-1 family, IL-1α, IL-β and IL-1ra share the same transporters (Gutierrez et
al., 1994), but IL-6 entry into brain is not inhibited by the presence of unlabeled IL-1α or TNF-α
(Banks et al., 1994), whereas competition studies with IL-1α, IL-1β, IL-6, and MIP-1a have
demonstrated selectivity of the TNF- α transporter (Gutierrez et al., 1994).
9.5. Role of Readily Diffusible Intermediates

The apparent lack of IL-1 receptors within neuronal elements in the PVN and the limited entry of
IL-1 into the CNS have led to the hypothesis that IL-1 stimulates the HPA axis via enhancing the
production of intermediates that directly interact with hypothalamic neurosecretory processes.
These intermediates include classical neurotransmitters, such as catecholamines, serotonin
(Gemma et al., 1991, Linthorst et al., 1994), histamine (Givalois et al., 1996, Knigge et al.,
1994), and more readily diffusible agents such as the lipid autacoids, eicosanoids, and the gase-
ous mediator nitric oxide (NO).
9.6. Cytokines Actions at Circumventricular Organs
Besides to cytokine entry into the CNS by way of carrier mediated transport or diffusion through
a disrupted BBB, a number of regions of CNS relatively devoid of a BBB permit cytokine inter-
action with neuronal elements. These CVO include structures lining the anteroventral border of
the third ventricle (AV3V) (namely, the OVLT and SFO), the ME, and the AP, posterior lobe of
the pituitary, subcommisural organ, and the pineal gland. Their capillaries do not form tight junc-
tions and are thus far more readily penetrable via the paracellular route (Gross and Weindl,
1987).
Circumventricular organs not only contain capillaries with far greater permeability than the rest
of the CNS, but the capillary density in these regions is extraordinarily high. Penetration of cyto-
kines into brain parenchyma within the CVO does not imply that they may diffuse to interact
with deeper brain structures, however, because tight junctions between modified ependymal cells
in these regions form a diffusion barrier between CVO and the rest of the brain. But these leaky
sites do provide a means with which cytokines such as IL-1 can influence neuronal activity in
these regions of the CNS (Johnson and Gross, 1993).

10. Conclusions and Recommendations
Cytokines are capable of influencing HPA axis secretory activity, with most having stimulatory
action. Cytokine receptors have been cloned, characterized and localized to many neuro endo-
crine tissues (hypothalamus, pituitary).
Central nervous system, pituitary and adrenal are capable of synthesizing a variety of cytokines,
whose levels are increased during endotoxemia. Recent studies suggesting that cytokine regula-
tion of the HPA axis may occur not only during infection, inflammation and trauma, but also
during psychological and physical stress.
Even though, the pituitary and adrenal glands represent potential targets of cytokine action on the
HPA axis during prolonged exposure, the majority of evidence indicates that either direct or indi-
rect stimulation of hypothalamic CRF secretion is the primary means by which the cytokines ac-
tivates the HPA axis.
The neuroanatomy and neuropharmacology pathways by which cytokines have been proposed to
influence the neuroendocrine hypothalamus are numerous and diverse. For example accurate
models of the mechanisms by which IL-1 activates the HPA axis have to take into account the
consistently reported inhibitory effects of either inhibitors of PG synthe sis or disruption of
catecholaminergic input into the hypothalamus.
Recommendations
1. Even though, numerous studies investigating the mechanisms of IL-1 induced activation
of the HPA axis, further studies on mechanisms of by which multiple cytokines (e.g., IL1
and IL-6) and another proinflammatory cytokines on HPA axis activation may strengthen
the evidence that how proinflammatory cytokines influence the HPA axis and vice versa.
2. The proposed mechanisms of activation of the HPA axis by cytokines have not explain
more on the effect of a single cytokine in response to a homeostatic threat. So that more
explanation requires to magnify the effect of single cytokine on the effect of the HPA ax-
is.

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