Relaçòes entre o sistema imunológico e o reprodutor parecem depender de liberação de leucócitos pelo baço, através de comando do LH. Observar as figuras ilustrativas.
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EIXO HIPÓFISE-OVÁRIO-BAÇO
1. Opinion
Pituitary–ovary–spleen axis in
ovulation
Oliver R. Oakley1, Michele L. Frazer2 and CheMyong Ko1
1
Division of Clinical and Reproductive Sciences, Department of Clinical Sciences, College of Health Sciences,
University of Kentucky, Lexington, Kentucky 40536, USA
2
Hagyards Equine Medical Institute, 4250 Iron Works Pike, Lexington, Kentucky 40511, USA
Leukocytes are rapidly recruited to the preovulatory ovary examine trafficking of leukocytes into the ovary, the re-
and play a crucial role as facilitators of ovulation and luteal quirement for leukocytes in ovulation, and consider in
formation. In this article, recent findings on leukocyte depth the spleen as a source of leukocytes.
trafficking to the ovary, as well as the physiological role
of leukocytes in the ovary, will be summarized and dis- Trafficking of leukocytes into the ovary
cussed. We then explore the novel hypothesis that the The migration of leukocytes in response to chemokines has
hypothalamus–pituitary–ovary (HPO) axis might include been implicated in a plethora of normal and pathophysio-
the spleen as a reservoir of leukocytes by summarizing logical aspects of reproductive systems [8]. Multiple che-
recent reports on this topic, both in the fields of immu- moattractants including interleukin-8 (IL-8) and a variety
nology and reproductive biology. of their target populations of leukocytes have been shown
to play important roles in ovulation [9–11]. Here we sum-
Linking leukocytes with ovulation marize ovarian leukocyte populations, their function and
Ovulation, a key step in the propagation of life, has always factors that affect their infiltration into the ovary.
been a subject of human curiosity. This egg-releasing act of
the ovary is still a mysterious event and much about the Leukocyte populations and their localization within the
process has yet to be unveiled. Ovulation is a crucial step in ovary
reproduction and has become a key therapeutic target for Traditionally, immunohistochemical techniques have been
treating female infertility and various ovarian diseases. used to characterize ovarian leukocyte populations. Al-
Ovulatory failure is associated with the development of though these methods are effective for identifying the
ovarian disorders such as polycystic ovarian syndrome localization of leukocytes in ovarian tissues, determining
(PCOS), hemorrhagic cyst formation, and hormonal imbal- the precise leukocyte subsets that are present in the tissue
ance, all of which are major risk factors in women’s health has been challenging. Modern techniques such as flow
[1–3]. Furthermore, controlling ovulation has become a cytometry have made it possible to distinguish between
hallmark for contraception because blockage of ovulation CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells,
ensures the absence of fertilizable eggs [4]. Understanding regulatory T cells or other cell types, each with different
the mechanisms that govern this ovulatory process, how- functions. Table 1 summarizes the leukocyte populations
ever, is challenging because there is interplay between the that have been identified in the ovary, their localization
reproductive system, the immune system, and possibly and possible functions. As shown in the table, most leuko-
other systems. Recently a comprehensive flow cytometry cyte subtypes are found in the ovary and are predominately
approach was applied to measure inflammation quantita- localized in the periphery of the follicle, interstitium, and
tively during ovulation by determining the spatiotemporal corpora lutea, but not inside follicles.
patterns of leukocyte infiltration in the ovaries of imma-
ture and adult rats. This effort led to the finding of massive Mechanism of leukocyte infiltration into the ovary
leukocyte infiltration into the ovary induced by the lutei- The initiator of an inflammatory event is often a discrete
nizing hormone (LH) surge or by human chorionic gonado- signal that is rapidly amplified by chemical signals pro-
tropin (hCG) injection during ovulation [5,6]. Surprisingly, duced by responding tissues and infiltrating cells. Unlike
ovarian leukocyte infiltration was accompanied by the during infection, where the inflammatory stimuli are ob-
release of millions of leukocytes into the bloodstream from vious, the initiating factors for an inflammatory response
the spleen, indicating that this immune organ might be a that occurs during a normal physiological event such as
source of leukocytes that infiltrate the preovulatory ovary. preovulatory inflammation are less clear. Infiltration and
Supporting this idea, recent studies showed that spleen distribution of leukocytes in the ovary are correlated with
leukocytes are recruited to injured heart tissues following hormonal changes associated with the estrous cycle
myocardial infarction [7]. Both of these studies demon- [12,13], indicating that reproductive hormones such as
strate the importance of the spleen as an immediate source ovarian steroids and gonadotropins can elicit inflammato-
of leukocytes for inflammatory events. In this article we ry responses in the ovary. The same adhesion molecules,
chemokines and cytokines observed in immune responses
Corresponding author: Ko, C. (cko2@uky.edu). to infectious agents are also found in the ovary during
1043-2760/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2011.04.005 Trends in Endocrinology and Metabolism, September 2011, Vol. 22, No. 9 345
2. Opinion Trends in Endocrinology and Metabolism September 2011, Vol. 22, No. 9
Table 1. Ovarian leukocyte species, localization and functions
Cell type Location Possible function(s) References
Monocyte/macrophage Periphery of follicles, tunica Il-8 secretion, luteal regression [5,22,99–111]
albugenia, corpora lutea
Neutrophils Theca layer, corpora lutea Production of proteolytic enzymes, [5,22,110,112,113]
ECM degradation, follicle maturation,
ovulation, luteal formation
Lymphocytes Hilus, stroma, corpora lutea Selection of dominant follicle, [5,101,107,110]
luteal formation, luteal regression
NK-cells Follicle, corpora lutea Angiogenesis [114]
Mast cells Medulla, cortex, interstitium, ECM degradation, ovulation [109,115,116]
corpora lutea
Eosinophils Theca layer, corpora lutea ECM degradation, neovascularization [111,116,117]
estrous [5,14,15], suggesting a similar mechanism of leu- the ovary are low, but production increases in granulosa
kocyte infiltration in the preovulatory ovary. The cytokines cells and theca cells upon LH stimulation [11]. IL-8 is also
interleukins (IL)-1, IL-6 and IL-10 could contribute to known to increase vascular permeability [19,20], and this
increased cell adhesion molecule (CAM) expression during could facilitate the infiltration process. In addition, the
ovulation [16]. Furthermore, our recent data show in- infiltrating leukocytes can interact with ovarian endothe-
creased expression of ICAM-1 and E-selectin corresponds lial cells and other cell types via a multitude of chemokines
with increased infiltration of leukocytes into the ovary [5]. during ovulation [21–23]. Treatment with neutralizing
Accordingly, treatment with IL-1 receptor antagonist (IL- antibodies to either IL-8 [24] or neutrophils [1] significant-
1Ra) inhibits hCG-induced ovulation rates in rats by 40% ly reduces ovulation rates in animal models.
[17]. Two chemokines, monocyte chemotactic protein-1
The classical four step process of tethering and rolling, (MCP-1, also known as chemokine C–C motif ligand
activation, firm adhesion and transmigration into the tis- CCL2) and thymus-expressed cytokine (TECK/CCL25),
sues is paramount to any event requiring infiltration of are well characterized in ovarian leukocyte infiltration.
leukocytes [18]; we anticipate ovulatory inflammation to be MCP-1 is a potent chemoattractant for monocytes and is
the same. Once the leukocytes are tethered on the endo- also effective in recruiting macrophages and T cells [25,26].
thelial cell wall, specific populations of leukocytes, charac- The major producers of MCP-1 are monocytes and macro-
terized by their chemokine receptor (CCR) expression, phages, although several other cell types including epithe-
migrate towards the source of the corresponding chemo- lial, endothelial, and smooth muscle cells have been shown
kine produced by theca cells (TC), granulosa cells (GC) or to produce this protein [27]. In addition to the chemotactic
resident ovarian leukocytes (Table 2). For instance, neu- properties, MCP-1 interacts with G-protein-coupled recep-
trophils infiltrate the ovary in response to an increased tors to induce multiple intracellular responses including
concentration gradient of IL-8 [9]. Amounts of basal IL-8 in activation and degranulation (a comprehensive review of
Table 2. List of chemokines, chemokine receptors and responsible cells present in the ovary
Chemokine Producing cells Chemokine receptor Responding cells References
CCL-2 (MCP-1) Mo/MF, cDC, BMDC, CCR-2a, b, T, Mo, baso, DC, NK [23,31,118–120]
GC, GLC, stromal fibroblast CCR-8, CCR-11
CCL-3 (MIP-1a) Mo/MF, cDC, BMDC, CCR-1, CCR-5 Mo/MF, T, baso, eos, neut, [118–120]
TE, TM, NK, B, GC, GLC DC, NK, GC, TC
CCL-4 (MIP-1b) Mo/MF, cDC, BMDC, CCR-5 Mo/MF, cDC, BMDC, B, T, [118–120]
TE, TM, NK, B NK, baso, eos, B, GC, TC
CCL-5 (RANTES) Mo/MF, cDC, BMDC, CCR-1, CCR-3, TE, TM, NK, Mo/MF, [118–120]
TE, GC, TM, NK CCR-5 DC, eos, baso, GC, TC
CCL-20(MIP-3a/LARC) Epithelial, GC CCR-6 PBMC, TE, TM, NKT, DC, B [118,121]
CCL25 (TECK) Mo/MF, cDC, BMDC, TC CCR-9 MF, thymocyte, DC, B [37,118]
CXCL-1 (Groa) Mo/MF, DC, BMDC, GC CXCR1, CXCR2 Neut, fibroblast [20,118,120]
CXCL-5 (ENA-78) BMDC CXCR2 Neut, endo, BMDC [120]
CXCL-8 (IL-8) Mast, GC, GLC, TC, CXCR1, CXCR2 Neut, baso, T, endo [20]
stromal fibroblast
CXCL-10 (IP-10) Osteoblasts, BM endo, GC CXCR3A CXCR3B T, NK, B, endo, Mo/MF, DC, GC [119,120]
CXCL-12 (SDF-1) BM reticular, GC, endo, CXCR4, CXCR7 CD34+ BM, thymocytes, [122,123]
stromal, fibroblast Mo/MF, TE, B, plasma,
neut, cDC, BMDC
CX3CL1 (Fractalkine) Mast cells, GC, TC and CX3CR1 NK, Mo, neut, mast, astrocytes, [118]
stromal fibroblasts, neurons, activated T cells
endothelium
Baso, basophil; BMDC, bone marrow-derived dendritic cell; cDC, conventional dendritic cell; DC, dendritic cell; endo, endothelial cell; GC, granulosa cell; GLC, granulosa-
lutein cell; NK, natural killer cell; neut, neutrophil; mast, mast cell; Mo, monocyte; MF, macrophage; PBMC, polymorphonuclear cell; TC, theca cell; TE, effector T cell; TM,
memory T cell.
346
3. Opinion Trends in Endocrinology and Metabolism September 2011, Vol. 22, No. 9
alternative functions for MCP-1 is given in [28]). Interest- Many immune mediators, such as cytokines, chemokines,
ingly, studies have demonstrated in humans and rats that cell surface receptors and adhesion molecules, are also
MCP-1 is involved in all aspects of ovarian function includ- substrates for MMP action [46]. In this regard, leukocyte-
ing follicular development [29,30], ovulation and luteolysis secreted MMPs might act both to break down the ECM and
[23,31]. Several studies have demonstrated that inhibiting to regulate the breakdown of chemotactic proteins, thereby
the production of monocytes/macrophages [32,33] or the limiting leukocyte infiltration
direct neutralization of ovarian macrophages [34] results Angiogenesis and neovascularization take place recur-
in reduced or inhibited ovulation rates in mice, further rently within the ovary, and vascular endothelial growth
supporting the role of monocytes/macrophages in ovula- factor (VEGF) expression closely correlates to the dynamic
tion. TECK was first described in the development of T changes that take place in the ovary. In particular, a dra-
cells in the thymus, but now has a well-accepted role as a matic increase in angiogenesis occurs before ovulation and a
chemokine that recruits cells to sites of inflammation fine network of capillaries develops and infiltrates the theca
[35,36]. Neutralization of TECK with specific antibodies layer. An increase also occurs immediately after ovulation to
inhibited leukocyte infiltration into the ovary by 85%, generate an extensive capillary network in the developing
resulting in a lack of ovulation. Interestingly, ovulatory corpus luteum (CL) [47]. The source of VEGF that drives this
failure has been attributed to the lack of infiltration of a active angiogenesis has not yet been clearly determined.
rare CD8a+ T cell population [37,38]. Consistent with this Although a body of literature suggests VEGF is expressed by
finding are reports that ovarian TECK expression is tightly TC, GC and the CL [48,49], monocytes, macrophages and
regulated by gonadotropins [39]. neutrophils also produce VEGF in many scenarios [50,51].
Two fascinating aspects of ovarian leukocyte infiltration Macrophages isolated from human follicular aspirates upre-
are the speed and extent to which it takes place. In rats, gulate VEGF production more than fivefold upon stimula-
this increased expression of CAMs and corresponding tion with hCG or LH [52]. Although the function of MMPs
infiltration commences in as little as 1–3 hours after and VEGF appear mutually exclusive, several investigators
ovulatory gonadotropin stimulation. This is an extremely have shown a mutual regulation between MMPs and VEGF
fast event, particularly in contrast to inflammation caused [53]. It is expected that more detailed information on the
by infection in which infiltration of leukocytes occurs over leukocyte function in the ovary will emerge as new assay
several days [40]. By contrast, preovulatory leukocyte methods and animal models are developed.
infiltration is not an occasional event but a frequent one
because leukocyte infiltration takes place each time ovula- HPO axis in regulating ovulation
tion occurs, which is every 4–5 days in rodents and ap- The hypothalamus, pituitary and ovary have long been
proximately once per month in women. considered to constitute the axis of a regulatory loop that
controls ovulation. These three key organs, the HPO axis,
Roles of ovarian leukocytes in ovulation communicate between one another via hormonal signals.
Leukocytes are involved in three main aspects of ovarian The result is cyclic hormonal changes that result in the
function: (i) loosening of the follicular wall to facilitate periodic expulsion of eggs in the process known as ovula-
follicle growth and ovulation, (ii) tissue repair following tion. Gonadotropin releasing hormone (GnRH) secreted
follicle rupture, and (iii) luteal formation and regression. from the hypothalamus stimulates pituitary gonadotrophs
Ovulation, as well as the events that follow, requires major to synthesize and release the gonadotropins, follicle-stim-
modifications in the extracellular matrix (ECM), and these ulating hormone (FSH) and LH. These two hormones then
rearrangements of the ECM involve tightly controlled exert their effects on the ovary, leading to the growth and
production of tissue proteases. Matrix metalloproteinases maturation of follicles and the expulsion of the oocyte [54–
(MMPs) are a family of soluble and membrane type (MT- 57]. The ovary is a complex organ, comprised of follicles
MMPs) zinc-dependent endopeptidases [41]. Both follicu- that are at different stages of development including the
lar cells (GC and TC) and leukocytes are known to produce quiescent primordial, primary, small pre-antral, antral,
MMPs [42–44]. However, further studies are needed for and large antral (or preovulatory) follicles. During follicu-
better characterization of the cells types responsible for lar growth, GCs surround the oocyte, a basement mem-
production of each MMP subtype. brane forms, and a TC layer develops and surrounds the
Leukocytes were recently described as major producers of follicle. The two cell layers act cooperatively in the produc-
MMP-9, the most abundant MMP found in the preovulatory tion of steroid hormones. TCs produce androgens that
ovary [45]. MMP-producing cells were identified as mono- traverse the basement membrane to the GCs, where aro-
cytes/macrophages and granulosa cells are the major pro- matase converts these androgens to estrogens that regu-
ducers of inhibitors of MMPs (TIMPs). In inflamed tissues, late FSH and LH release from the pituitary [54].
as monocytes move through tissue they secrete MMPs that
digest matrix proteins, facilitating migration through tis- Inflammation and ovulation
sues to the sites of inflammation. It is feasible that ovarian Many hallmarks of inflammation are also observed in the
monocytes produce one class of MMPs for migration pur- ovary at the time of ovulation. Similar vascular changes
poses and, upon tissue specific differentiation, produce more include increased blood flow and vascular permeability,
potent MMPs that could further facilitate matrix break- and cellular events such as increased leukocyte extravasa-
down. Interestingly, although the major role of MMPs in the tion and activation occur at the site of inflammation and in
ovary is related to their function in ECM breakdown, the the ovulating ovary. In addition, chemical mediators in-
substrates for MMPs are not restricted to matrix proteins. cluding prostaglandins, vasoactive amines (histamine and
347
4. Opinion Trends in Endocrinology and Metabolism September 2011, Vol. 22, No. 9
serotonin), cytokines and chemokines are produced both in In particular, the ovary utilizes the same molecular signals
inflammatory responses and ovulation. The characteristic that attract leukocytes via the mechanism that governs
tissue damage, repair and remodeling that result from their infiltration at the site of infections or injuries
inflammation in non-ovarian tissues also occur in the [11,15,74,75]. Thus, does the spleen serve as a source of
ovary during ovulation [58–64]. Therefore, ovulation is infiltrating leukocytes during this period of ovulatory in-
now considered an outcome of acute inflammatory reac- flammation? To answer this question, a study recently
tions in the ovary. measured sequential changes of leukocyte content in the
Leukocytes as the main mediators of ovarian inflamma- ovary and spleen after inducing superovulation, by inject-
tory responses are a major target of investigation. Leuko- ing gonadotropins [a bolus injection with pregnant mare
cytes circulate in the blood, become attracted by serum gonadotropin (PMSG) to stimulate follicular growth
chemokines and adhesion molecules in inflamed tissues, followed 48 h later by hCG injection to induce ovulation]
and traverse the blood vessel wall infiltrating interstitial [5]. Flow cytometry was employed to count the actual
tissues to reach their sites of action. Cytokines that are numbers of leukocytes in these two distal organs using
initially released by the inflamed tissue play a crucial role CD45-specific fluorescent antibodies. This approach
in increasing adhesion molecule expression on endothelial revealed that as intraovarian leukocyte numbers in-
cells and in upregulating the corresponding receptor ex- creased, leukocyte numbers in the spleen decreased sharp-
pression on leukocytes, both of which greatly enhance ly. The same inverse relationship was observed in adult
leukocyte migration to the target tissues [65,66]. At sites rats during the period of proestrus to estrus, when ovula-
of inflammation, leukocytes and vascular endothelial cells tory inflammation occurs. Lower numbers of leukocytes
release chemokines and cytokines that accelerate leuko- infiltrated the ovary upon superovulation induction in
cyte recruitment and modulate leukocyte function. Even- splenectomized rats [5]. Together, these findings strongly
tually, however, the main function of leukocytes in the indicate that the spleen supplies leukocytes to the preovu-
ovary is exerted through release of proteases [67,68]. A latory ovary.
number of molecules, including diverse cytokines, chemo- These findings raise the interesting question, should the
kines, and proteases that are commonly associated with spleen be considered a key component of the reproductive
immunological responses, are present in the preovulatory axis in regulating ovulation? Are spleen leukocytes under
human ovary as well as in ovaries in animal models [60– the regulation of LH, progesterone and/or prostaglandins
63]. Therefore, the past 30 years of research have clearly whose ovarian functions are crucial for successful ovula-
demonstrated the significance of infiltrating leukocytes in tion? How does the HPO axis communicate with the spleen
ovarian function. Much of this work implies that the to trigger the preovulatory leukocyte release? Unfortu-
infiltration of leukocytes in periovulatory period is a key nately, none of these questions can be clearly answered
event in ovulation [69]. However, the origin of these infil- at present because very little research on the spleen has
trating leukocytes, their phenotype, and the mechanisms been done in relation to its reproductive function. However,
that govern their trafficking to the ovary are elusive. a glimpse of the role the spleen might play in ovulation can
be gathered from past and current literature.
Adding the spleen to the HPO axis
Leukocytes are hematopoietic in origin and are produced in The impact of splenectomy on female fertility
the bone marrow. Upon release into the bloodstream they The removal of the entire spleen, splenectomy, has been a
circulate and infiltrate inflamed tissues or are stored in successful surgical procedure for many hematological, im-
lymphoid organs, such as the spleen, for future activation munological, and traumatic conditions. However, although
and release. The spleen releases leukocytes following in- the removal is advantageous in treating the specific dis-
duction of acute inflammation in the heart by ischemic orders, it leaves the patient with a significant defect in both
myocardial injury [7,70,71]. Using a sophisticated ap- innate and adaptive immune responses. As a consequence,
proach that involved the transplantation of spleens from splenectomized patients have a 60–100-fold increased risk
GFP mice into wild-type mice, it was demonstrated that of sepsis [76]. The ovulatory consequences of splenectomy
spleen leukocytes infiltrate heart tissues during acute in humans, however, are difficult to assess because other
inflammation. This finding indicates that at least one role treatment regimens such as chemotherapy or radiotherapy
of the spleen is to act as an immediate supplier of leuko- that often accompany the splenectomy procedure also
cytes for tissues that experience acute inflammation. This result in severe damage to ovulatory function. However,
concept is supported by the fact that, upon stimulation by there are several animal studies that indicate a role of the
an inflammatory signal, the bone marrow takes days to spleen in ovarian function. In particular, studies in rodents
produce leukocytes whereas spleen leukocytes reach sites and rabbits show that splenectomy results in either a delay
of inflammation within minutes to hours [7,72,73]. in ovulation [77], aberrant corpus luteal function [78], or an
Upon ovulatory gonadotropin stimulation the ovary absence of leuteolysis [79,80].
experiences an acute inflammatory response. This inflam-
mation is different from responses to infectious insults Proposed method of communication between the HPO
because ovulatory inflammation is in response to a normal axis and the spleen
physiological event, LH stimulation. However, the nature How would the HPO axis communicate with spleen to
and sequence of the inflammatory events occurring in the induce spleen leukocyte release? Because leukocytes are
preovulatory ovary are essentially identical to those reac- released as early as one hour after ovulatory LH surge, LH
tions taking place at the sites of infectious inflammation. could directly stimulate spleen (Figure 1). However, this is
348
5. [()TD$FIG] Opinion Trends in Endocrinology and Metabolism September 2011, Vol. 22, No. 9
Hypothalamus Hypothalamus
Anterior pituitary
GnRH
?
Pituitary
Spleen
E2 LH
?
Leukocytes
Ovary
TRENDS in Endocrinology & Metabolism
Figure 1. Proposed interplay between the HPO axis and spleen. Preovulatory rise of E2 (estradiol) stimulates release of LH into the bloodstream. LH then triggers leukocyte
release from the spleen either by acting directly on leukocytes or through indirect effects on spleen tissues. Spleen leukocytes released into the bloodstream migrate to the
ovary in response to cytokines and chemokines that act as leukocyte attractants; the cells then enter the tissue through interactions between leukocyte receptors and
adhesion molecules on the endothelial cells.
[()TD$FIG]
White pulp
Spleen
MZ
Red pulp
Theca cells
Ovary
Granulosa cells
Key: Chemokine receptors Chemokines Leukocyte expressed CAM Endothelial cell expressed CAM
TRENDS in Endocrinology & Metabolism
Figure 2. Spleen leukocyte trafficking to the ovary. Spleen reservoir leukocytes are tethered in the open blood system of the red pulp through either specific chemokine–
chemokine receptor or adhesion-molecule interactions. Upon LH surge, changes in leukocyte CCR expression or the reduced chemokine production by reticular fibroblast within
the red pulp results in the mobilization of spleen reservoir leukocytes into the bloodstream. Upon arriving at the ovary, LH-mediated upregulation of adhesion molecule
expression on ovarian endothelial cells, together with LH-mediated vasodilation, increases leukocyte adherence to the endothelial cells. Once tethered to the ovarian endothelial
cells, leukocytes respond to follicle-produced chemokines. The migration of leukocytes through the interstitial space towards the source (GC, TC or ovarian leukocytes) results in
the production of MMPs to facilitate movement through the ECM. At the mature follicle, leukocytes become activated by locally produced cytokines and produce reactive oxygen
species (ROS), MMPs and proteolytic granules that weaken the basement membrane of the follicle, enabling the release of the oocyte. MZ, marginal zone.
349
6. Opinion Trends in Endocrinology and Metabolism September 2011, Vol. 22, No. 9
unlikely because the presence of LH receptors in the spleen Concluding remarks
is reported only in poultry [81], and the spleen does not The immune system is not only important for battling
express LH receptors in mammals [82]. Instead, an endo- foreign invaders but is also essential for female reproduc-
crine molecule(s) produced by the ovary in response to LH tion. We propose here that the spleen can bridge the
stimulation could travel to the spleen via the circulation immune and reproductive systems by serving as a reser-
and stimulate leukocyte release (Figure 1). In the case of voir for the leukocytes required for the inflammatory
the myocardial injury model, angiotensin (Ang) II was events that regulate ovulation. Rigorous collaborative
shown to have such activity [7]. It will be interesting to studies between the fields of immunology and reproductive
determine if Ang II has this role in the periovulatory biology will be required to validate this hypothesis and
release of spleen leukocytes. In support of the potential elucidate the interaction between the reproductive organs
role of angiotensin II, studies indicate that ovarian Ang II and the spleen.
synthesis and secretion increases immediately after ovu-
latory LH/hCG stimulation and ovulation is inhibited if Acknowledgments
We thank Dr. Thomas E. Curry for critical comments and Mr. Tom Dolan
PD123319 or Saralasin, Ang II receptor antagonists, are
for the artwork. This work was supported by National Institutes of
injected into superovulation-induced rabbits and rats, re- Health grant RO1HD052694 (to C.K.).
spectively [83–85]. Other candidate molecules that could
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