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Inflammatory pathways linking obesity and ovarian dysfunction
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Symposium Abstracts / Journal of Reproductive Immunology 86 (2010) 11–34
Furthermore, increased bacterial lysis in response to the antibiotic might actually enhance agonism of the innate immune system. In this talk I will discuss the proposition that in pregnancies at risk of inflammation-driven preterm labour, administration of anti-inflammatory drugs is a viable therapeutic option to prevent sPTB and improve fetal outcomes. Preventing fetal inflammation via administration of placenta-permeable drugs could also have significant perinatal benefits in addition to those related to extension of gestational age, as a fetal inflammatory response is associated with a range of significant morbidities. A number of potential drugs are available, effective against different aspects of the inflammatory process, which may be viable modalities in this context; these will be discussed, together with potential safety concerns associated with administration of anti-inflammatory agents in pregnancy. doi:10.1016/j.jri.2010.06.016 S13 Toll-like receptors and inflammatory signalling in spermatogenesis and testicular immune regulation M.P. Hedger Monash Institute of Medical Research, Monash University, Clayton, Australia While it is self-evident that infection and inflammation in the reproductive tract can inhibit male fertility, the observation that fertility is also compromised by systemic inflammation and disease is a basic conundrum of male reproductive biology. However, recent studies implicating microbial pattern-recognition receptors, such as the Toll-like receptors (TLRs), as well as inflammatory signalling pathways and cytokines in testicular function have cast new light on this mysterious link between inflammation and reproduction. Spermatogenesis is a complex, organized and highly regulated process involving intimate interactions between the developing germ cells and supporting Sertoli cells. Sertoli cells express several TLRs and respond to TLR ligands by producing a number of inflammatory cytokines and mediators, in particular interleukin-1␣ (IL-1␣), IL6 and nitric oxide (NO), as well as immunoregulatory cytokines, such as activin A. Not only do these molecules regulate spermatogonial/spermatocyte development and many critical supportive functions of the Sertoli cells, but their production varies across the cycle of the seminiferous epithelium, with significant changes in expression coinciding with key events within the cycle. The possibility that this cyclical production may occur in response to endogenous TLR ligands expressed by the developing germ cells has important implications for understanding normal spermatogenic regulation. Inflammatory signalling pathways activated by TLR ligands appear to play fundamental roles in regulating Sertoli cell activity and responses to reproductive hormones, as well as regulation of immune events within the testis. Moreover, such relationships between inflammatory signalling
and spermatogenesis provide a potential mechanism to account for the link between infection/inflammation and testicular dysfunction. At least some of the negative effects of inflammation on spermatogenesis may be attributed to elevated production of inflammatory mediators within the circulation and the testis, which exert disruptive effects on germ cell development and survival, and the ability of Sertoli cells to provide support. doi:10.1016/j.jri.2010.06.017 S14 Inflammatory pathways linking obesity and ovarian dysfunction R.L. Robker Robinson Institute, University of Adelaide, Adelaide, SA, Australia Obesity is characterized by chronic low-level inflammation. Abdominal fat is infiltrated by immune cells and releases adipose tissue-specific cytokines (adipokines) that affect systemic insulin sensitivity and lipid utilization. Obese women often experience reduced pregnancy rates, and even with assisted reproduction have fewer oocytes retrieved and lower success rates. We have sought to understand how alterations in the ovarian environment of obese females leads to impaired oocyte maturation and early embryo development. Female mice fed high fat diet exhibit weight gain, immune cell infiltration into adipose and elevated inflammatory markers. Intracellular fat also accumulates in ovarian cells; oocytes in particular are larger and contain dramatically more lipid than oocytes from mice fed control diet. Lipid accumulation is associated with induction of lipotoxicity responses, including endoplasmic reticulum (ER) stress, increased expression of TNF␣, IL-6 and IL-1, and apoptosis. Further, ovulation and fertilization rates are reduced. To determine whether similar events occur in ovaries of obese women, follicular fluid and granulosa/cumulus cells were obtained from women of varying body mass indices (BMIs) undergoing assisted reproduction treatment. Analysis of granulosa and cumulus cells revealed similar expression of genes involved in insulin signaling and lipid transport, but increased expression of ER stress marker ATF4 in granulosa cells from obese women compared to levels in non-obese women. Follicular fluid of obese women contained high levels of triglyceride, free fatty acids, cytokines, adipokines and C-reactive protein. When follicular fluid from obese women was used as maturation media for mouse oocytes, the oocytes accumulated lipid, ER stress was induced and oocyte maturation was blocked. Follicle fluid from moderate weight women or culture in lipid-rich media did not elicit these effects. Thus there are marked changes in the ovarian environment of obese women, with heightened inflammation likely contributing to defects in oocyte developmental competence. doi:10.1016/j.jri.2010.06.018
Symposium Abstracts / Journal of Reproductive Immunology 86 (2010) 11–34
Furthermore, increased bacterial lysis in response to the antibiotic might actually enhance agonism of the innate immune system. In this talk I will discuss the proposition that in pregnancies at risk of inflammation-driven preterm labour, administration of anti-inflammatory drugs is a viable therapeutic option to prevent sPTB and improve fetal outcomes. Preventing fetal inflammation via administration of placenta-permeable drugs could also have significant perinatal benefits in addition to those related to extension of gestational age, as a fetal inflammatory response is associated with a range of significant morbidities. A number of potential drugs are available, effective against different aspects of the inflammatory process, which may be viable modalities in this context; these will be discussed, together with potential safety concerns associated with administration of anti-inflammatory agents in pregnancy. doi:10.1016/j.jri.2010.06.016 S13 Toll-like receptors and inflammatory signalling in spermatogenesis and testicular immune regulation M.P. Hedger Monash Institute of Medical Research, Monash University, Clayton, Australia While it is self-evident that infection and inflammation in the reproductive tract can inhibit male fertility, the observation that fertility is also compromised by systemic inflammation and disease is a basic conundrum of male reproductive biology. However, recent studies implicating microbial pattern-recognition receptors, such as the Toll-like receptors (TLRs), as well as inflammatory signalling pathways and cytokines in testicular function have cast new light on this mysterious link between inflammation and reproduction. Spermatogenesis is a complex, organized and highly regulated process involving intimate interactions between the developing germ cells and supporting Sertoli cells. Sertoli cells express several TLRs and respond to TLR ligands by producing a number of inflammatory cytokines and mediators, in particular interleukin-1␣ (IL-1␣), IL6 and nitric oxide (NO), as well as immunoregulatory cytokines, such as activin A. Not only do these molecules regulate spermatogonial/spermatocyte development and many critical supportive functions of the Sertoli cells, but their production varies across the cycle of the seminiferous epithelium, with significant changes in expression coinciding with key events within the cycle. The possibility that this cyclical production may occur in response to endogenous TLR ligands expressed by the developing germ cells has important implications for understanding normal spermatogenic regulation. Inflammatory signalling pathways activated by TLR ligands appear to play fundamental roles in regulating Sertoli cell activity and responses to reproductive hormones, as well as regulation of immune events within the testis. Moreover, such relationships between inflammatory signalling
and spermatogenesis provide a potential mechanism to account for the link between infection/inflammation and testicular dysfunction. At least some of the negative effects of inflammation on spermatogenesis may be attributed to elevated production of inflammatory mediators within the circulation and the testis, which exert disruptive effects on germ cell development and survival, and the ability of Sertoli cells to provide support. doi:10.1016/j.jri.2010.06.017 S14 Inflammatory pathways linking obesity and ovarian dysfunction R.L. Robker Robinson Institute, University of Adelaide, Adelaide, SA, Australia Obesity is characterized by chronic low-level inflammation. Abdominal fat is infiltrated by immune cells and releases adipose tissue-specific cytokines (adipokines) that affect systemic insulin sensitivity and lipid utilization. Obese women often experience reduced pregnancy rates, and even with assisted reproduction have fewer oocytes retrieved and lower success rates. We have sought to understand how alterations in the ovarian environment of obese females leads to impaired oocyte maturation and early embryo development. Female mice fed high fat diet exhibit weight gain, immune cell infiltration into adipose and elevated inflammatory markers. Intracellular fat also accumulates in ovarian cells; oocytes in particular are larger and contain dramatically more lipid than oocytes from mice fed control diet. Lipid accumulation is associated with induction of lipotoxicity responses, including endoplasmic reticulum (ER) stress, increased expression of TNF␣, IL-6 and IL-1, and apoptosis. Further, ovulation and fertilization rates are reduced. To determine whether similar events occur in ovaries of obese women, follicular fluid and granulosa/cumulus cells were obtained from women of varying body mass indices (BMIs) undergoing assisted reproduction treatment. Analysis of granulosa and cumulus cells revealed similar expression of genes involved in insulin signaling and lipid transport, but increased expression of ER stress marker ATF4 in granulosa cells from obese women compared to levels in non-obese women. Follicular fluid of obese women contained high levels of triglyceride, free fatty acids, cytokines, adipokines and C-reactive protein. When follicular fluid from obese women was used as maturation media for mouse oocytes, the oocytes accumulated lipid, ER stress was induced and oocyte maturation was blocked. Follicle fluid from moderate weight women or culture in lipid-rich media did not elicit these effects. Thus there are marked changes in the ovarian environment of obese women, with heightened inflammation likely contributing to defects in oocyte developmental competence. doi:10.1016/j.jri.2010.06.018