Although progesterone action is essential throughout pregnancy, its details remain unclear. Under the influences of progesterone, a receptive uterus undergoes stromal proliferation and epithelial differentiation, which are critical endometrial changes for successful embryo implantation. In this review article, we have outlined the recent findings about roles and regulation of progesterone signaling in uterine receptivity and embryo implantation.

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Background: Testis is known as one of the immunologically privileged organs. In particular, blood-testis barrier formed by Sertoli cells protects autoimmunogeneic spermatozoa and spermatid from attack by the self-immune system. Moreover, it was demonstrated that Sertoli cells, Leydig cells and a few population of testicular macrophages exhibit immunosuppressive activity. Recent studies also suggest a possibility that some cytokines in the testis contribute to maintaining the immune privilege. Interleukin (IL)-35 is a heterodimeric cytokine composed of Epstein-Barr virus-induced gene 3 (EBI3) and the p35 subunit of IL-12. Although it is IL-35 has an important role in immunosuppression, its role in the testis remains unknown. Methods and Findings: In the present study, we investigated the role of intra-testicular IL-35 by histochemistry, immunohistochemistry and real-time RT-PCR using wild-type C57BL/6 mice and EBI3- and p35-deficient mice. EBI3 expression was detected in a part of CD163-positive macrophages and acrosomal regions of spermatids in testis of wild-type mice. Intriguingly, p35 expression was coincidently detected in a part of EBI3- and F4/80-positive macrophages, and also in basal lamina of seminiferous tubules, endothelial cells and acrosomal region of spermatids. A significant increase in the number of seminiferous tubules with spermatogenic disturbance was observed in both EBI3- and p35-deficient mice, compared with that in wild-type mice. Especially, p35-deficient mice showed severe spermatogenic disturbance. Moreover, CD4-, CD8- and B220-positive infiltrating cells were detected in the testicular interstitium of EBI3- and p35-deficient mice, but not of wild-type mice. Intra-testicular mRNA expression of interferon-gamma was significantly increased in EBI3- and p35-deficient mice. A similar increase in the expression of IL-10 was observed only in p35-deficient mice. Finally, autoantibodies to spermatids were detected in sera obtained from EBI3- and p35-deficient mice, but not from wild-type mice. Conclusions: In testis, there are EBI3- and p35-double positive macrophages, possibly producing immunosuppressive IL-35. And, lack of either EBI3 or p35 causes infiltration of lymphocytes into testis and spermtatogenic disturbance. These results indicate that IL-35 plays an important role in maintaining the testicular immune privilege.

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Objectives: Endometriosis frequently develops in the female pelvic cavity. This suggests that the peritoneal environment that contains various free-floating cells such as macrophages and endometrial cells derived from refluxed menstrual blood may contribute to the development of endometriosis. We previously reported that the proportion of active macrophages was elevated in ascites from patients with endometriosis, and in another study, activated macrophages reportedly released several cytokines into the peritoneal cavity. This study focused on the interactions between macrophages and endometrial stromal cells (ESCs) in the development of endometriosis.Methods: The phenotype of macrophages in the ascites from patients with endometriosis was determined by immunocytochemistry. Soluble factors in ascites and conditioned medium from human macrophages and ESCs in co-culture system were quantified by the Cytokine Array Kit. Next, we investigated the significance of macrophages for proliferation and Stat3 activation of ESCs by using co-cultured cells. Furthermore, pSTAT3 expression of peritoneal foci of endometriosis was assessed by immunohistochemistry. Finally, the effects of corosolic acid (CA), a triterpenoid compound, on proliferation and Stat3 activation of ESCs in co-cultures were evaluated.Results: The total number of CD163+ macrophages (M2 macrophages) in ascites from the endometriosis group was significantly higher than that of the control group. The cytokine array study detected that the production of GM-CSF, RANTES, IL-1 receptor antagonist, and MCP-1 were up-regulated in ascites from patients with endometriosis and in conditioned medium from co-cultured cells (c-CM). Co-culture with M2 macrophages significantly up-regulated ESC proliferation and Stat3 activation in ESCs in vitro. Immunohistochemically, Stat3 was activated in both epithelial and stromal cells in endometriotic lesions. When the inhibitory effect of a Stat3 inhibitor, CA on ESC was investigated, CA inhibited ESC proliferation and Stat3 activation induced by c-CM.Conclusions: These findings indicated that the interactions between M2 macrophages and ESCs via Stat3 activation may play indispensable roles in the development of endometriosis. Targeting Stat3 signals may aid the treatment of patients with endometriosis.

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