| interleukin 6 | OKDB#: 396 |
| Symbols: | IL6 | Species: | human | ||
| Synonyms: | CDF, HGF, HSF, BSF2, IL-6, BSF-2, IFNB2, IFN-beta-2 | Locus: | 7p15.3 in Homo sapiens |
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| General Comment |
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Rodier F et al. (2009) Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signalling, usually associated with senescence, not after transient DNA damage responses (DDRs). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell-cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Furthermore, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell-cycle checkpoints and DNA repair, a new and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.//////////////////The ever-expanding myokinome: discovery challenges and therapeutic implications. Whitham M et al. (2016) Exercise reduces the risk of a multitude of disorders, from metabolic disease to cancer, but the molecular mechanisms mediating the protective effects of exercise are not completely understood. The realization that skeletal muscle is an endocrine organ capable of secreting proteins termed 'myokines', which participate in tissue crosstalk, provided a critical link in the exercise-health paradigm. However, the myokine field is still emerging, and several challenges remain in the discovery and validation of myokines. This Review considers these challenges and highlights some recently identified novel myokines with the potential to be therapeutically exploited in the treatment of metabolic disease and cancer. IL6 is a prototypic myokine.//////////////////
The human interleukin-6/interferon-beta 2 gene (IFNB2) product is identical to that for the B-cell stimulation factor-2 (BSF-2), the
hybridoma growth factor (HGF), and the hepatocyte stimulating factor (HSF). Proteins derived from this gene mediate the plasma protein response to tissue injury (acute-phase response) and regulate the growth and differentiation
of both B and T cells.
NCBI Summary: This gene encodes a cytokine that functions in inflammation and the maturation of B cells. In addition, the encoded protein has been shown to be an endogenous pyrogen capable of inducing fever in people with autoimmune diseases or infections. The protein is primarily produced at sites of acute and chronic inflammation, where it is secreted into the serum and induces a transcriptional inflammatory response through interleukin 6 receptor, alpha. The functioning of this gene is implicated in a wide variety of inflammation-associated disease states, including suspectibility to diabetes mellitus and systemic juvenile rheumatoid arthritis. Elevated levels of the encoded protein have been found in virus infections, including COVID-19 (disease caused by SARS-CoV-2). [provided by RefSeq, Aug 2020] |
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| General function | Ligand, Cytokine | ||||
| Comment | The Role of IL-6 Trans-Signaling in Vascular Leakage: Implications for Ovarian Hyperstimulation Syndrome in a Murine Model. Wei LH et al. Context:The inflammatory cytokine IL-6 is related to ovarian hyperstimulation syndrome (OHSS), although the functional role of IL-6 in OHSS remains largely unknown.Objective:A key feature of the IL-6 response is that its regulation is dependent on IL-6 trans-signaling via soluble IL-6 receptor-a (sIL-6Ra). The objective of the study was to elucidate the mechanistic role of IL-6 trans-signaling in the vascular leakage that underlies the pathophysiology of OHSS.Design:Ovarian endothelial cells (ECs) and granulosa-lutein cells were obtained from women undergoing in vitro fertilization. OHSS was induced in mice by administering gonadotropins for 2 days followed by human chorionic gonadotropin. The functional role of IL-6 trans-signaling in OHSS was verified using the designer cytokines Hyper IL-6 and sgp130-Fc.Results:The follicular fluid levels of sIL-6Ra were elevated in women at high risk for OHSS. In the murine OHSS model, stimulation with gonadotropins significantly induces ovarian IL-6 and sIL-6Ra expression. In vitro, FSH induces de novo sIL-6Ra synthesis in granulosa-lutein cells through a protein kinase C-dependent pathway. In addition, sIL-6Ra was released by leukocytes in the presence of conditioned medium from human chorionic gonadotropin-treated granulosa-lutein cells. Ovarian ECs responded to the IL-6Ra-IL-6 complex (Hyper IL-6) but not to IL-6 alone. With activation of signal transducer and activator of transcription 3 (STAT3) and ERK, Hyper IL-6 increased vascular endothelial growth factor expression and the vascular permeability of ECs. Selective blockade of IL-6 trans-signaling by sgp130-Fc significantly inhibited vascular endothelial growth factor expression and prevented OHSS in mice.Conclusions:IL-6 trans-signaling is activated during the ovarian stimulation process. Our findings provide insight into the biologic effects of IL-6 trans-signaling in OHSS and highlight that IL-6 trans-signaling can induce vascular leakage in this disease. | ||||
| Cellular localization | Secreted, SNP | ||||
| Comment | candidate123 | ||||
| Ovarian function | Antral follicle growth, Cumulus expansion, Follicle atresia, Ovulation, Steroid metabolism, Luteolysis, Oocyte maturation | ||||
| Comment | Interleukin-6 supplementation improves post-transfer embryonic and fetal development of in vitro-produced bovine embryos. Seekford ZK et al. (2021) The use of in vitro produced embryos in dairy and beef cattle has increased in recent years, but compromised post-transfer pregnancy success prevents producers from capturing all the benefits this technology can provide. This study explored whether supplementing interleukin-6 (IL6) during in vitro embryo development influences post-transfer development of the embryo-proper, fetus and placenta during early gestation in cattle. Slaughterhouse-derived cumulus oocyte complexes underwent IVM (day -1) and IVF (day 0). On day 5 post-fertilization, embryos were treated with either 0 (CONT) or 100 ng/mL recombinant bovine IL6. No difference in blastocyst formation was detected on day 7.5 post-fertilization, but an increase (P < 0.05) in inner cell mass cell numbers and tendency for increased (P = 0.08) trophectoderm cell numbers were detected in IL6-treated blastocysts. A subset of the blastocysts was loaded individually into transfer straws, and embryo transfer (ET) was completed using estrous cycle stage-matched, nonlactating commercial beef and dairy cows. A subset of cows from each group underwent timed artificial insemination (TAI). Pregnancy rates were similar among all three treatment groups at day 28 and 70. No differences in crown-rump length (CRL), crown nose length (CNL), abdominal diameter (AD), or placental fluid volume (PFV) were detected between TAI and ET-IL6 groups. Reductions (P < 0.05) in CRL and AD were detected at day 56 and a tendency for a reduction (P = 0.08) in PFV was detected on day 35 when comparing the ET-CONT group with the TAI group. Reductions (P < 0.05) in CRL and PFV on day 28 and CNL and AD on day 56 as well as a tendency for a reduction (P = 0.08) in PFV on day 35 were detected when contrasting ET-CONT with ET-IL6. Circulating plasma pregnancy-associated glycoprotein concentrations were similar among all treatment groups. In summary, IL6 treatment to IVP embryos before ET produced pregnancies that more closely resembled TAI-generated pregnancies than pregnancies generated using conventionally cultured embryos. These findings failed to find any adverse effects of IL6 supplementation on early development of the embryo-proper and fetus or on placental activity. Rather, these observations suggest that IL6 treatment may normalize the developmental trajectory of the embryo-proper and fetus for in vitro produced embryos.//////////////////Interleukin 6 in follicular fluid reduces embryo fragmentation and improves the clinical pregnancy rate. Yang J et al. (2020) The aim of this study was to evaluate the role of interleukin 6 in embryo development in the in vitro fertilization cycles. This was a retrospective cohort study. One hundred and three women undergoing in vitro fertilization and embryo transfer due to a tubal factor were included in the study. The follicular fluid IL-6 levels on oocyte retrieval day from each patient were determined by ELISA. The relationships between follicular fluid IL-6 levels and IVF cycle parameters were investigated. The levels of follicular fluid IL-6 were not affected by the use of drugs for superovulation or by estrogen. In addition, follicular fluid IL-6 levels did not affect the number of oocytes retrieved or the MII oocyte rate. High levels of follicular fluid IL-6 correlated with a significant increase in the rates of clinical pregnancy. Follicular fluid IL-6 levels did not affect the cell number or the blastomere symmetry of day 3 embryos, but it did significantly reduce the embryo fragmentation rate. High levels of follicular fluid IL-6 improved the rates of clinical pregnancy and reduce embryo fragmentation.//////////////////IL-6 Promotes FSH-Induced VEGF Expression Through JAK/STAT3 Signaling Pathway in Bovine Granulosa Cells. Yang M et al. (2017) Vascular endothelial growth factor (VEGF) has been demonstrated to play a pivotal role in the regulation of angiogenesis in ovarian follicular development, particularly during the preovulatory period. Although numerous studies have shown that interleukin-6 (IL-6) is one of the major inducing factors that regulate the expression of VEGF in non-ovarian cells, whether it involved in regulating the expression of VEGF in normal ovarian granulosa cells is still unknown. The aim of this study was to elucidate the mechanisms underlying the effect of IL-6 on FSH-induced VEGF expression in bovine granulosa cells derived from large follicles. VEGF mRNA expression in granulosa cells after IL-6 with/without inhibitors treatment was analyzed by RT-qPCR. Phosphorylation levels of ERK1/2 and STAT3 proteins induced by IL-6 were analyzed by western blotting. The protein levels produced by granulosa cells were detected by ELISA. High concentration of IL-6 (10ng/ml) can significantly up-regulate FSH-induced VEGF gene and protein expression levels in granulosa cells, and also promote the VEGF upstream regulators HIF-1α and COX2 mRNA expression. VEGF expression levels were significantly decreased after specifically blocking HIF-1α and COX2 by using inhibitors. The up-regulation effect of IL-6 on FSH-induced VEGF expression in granulosa cells mainly through activating the JAK/STAT3 signaling pathway, which can be impaired by JAK inhibitors. IL-6 can promote FSH-induced VEGF expression in granulosa cells, which is mainly achieved by increasing the expression of HIF-1α and COX2.This promoting effect is mediated by activating the JAK/STAT3 pathway. Moreover, there may be a synergistic relationship between FSH and IL-6 in the regulation of VEGF expression.////////////////// Enhanced Inflammatory Transcriptome in the Granulosa Cells of Women with Polycystic Ovarian Syndrome. Adams J et al. (2016) Polycystic ovarian syndrome (PCOS), the most common endocrine disorder of reproductive aged women, is associated with systemic low-grade inflammation. We propose that increased or altered intra-follicular inflammatory reactions also occur in peri-ovulatory follicles of PCOS patients. Gene profiling and qPCR analyses in granulosa-lutein cells (GCs) collected from PCOS and non-PCOS women undergoing IVF were compared with serum and follicular fluid (FF) levels of cytokines and chemokines. University-based. 21 PCOS and 45 control patients were recruited: demographic, hormone, BMI and pregnancy outcomes were abstracted from patient data files. GC cytokine/chemokine mRNAs were identified and analyzed by gene-chip microarrays/qPCR prior to and following culture with hCG, DHT, IL-6, or IL-8; serum/FF cytokine levels were also analyzed. Relative serum/FF cytokine levels and GC cytokine expression before and after culture were compared and related to BMI. PCOS GCs express elevated transcripts encoding cytokines, chemokines and immune cell markers, 2) based on gene profiling and qPCR analyses, obese PCOS patients define a distinct PCOS disease subtype with the most dramatic increases in proinflammatory and immune related factors and 3) hCG and DHT increased cytokine production in cultured GCs whereas cytokines augmented cytokine and vascular genes, indicating that hyperandrogenism/elevated LH and obesity in PCOS women augments intra-follicular cytokine production. Intra-follicular androgens and cytokines likely comprise a local regulatory loop that impacts GC expression of cytokines and chemokines and the presence of immune cells; this loop is further enhanced in the obese PCOS subtype.////////////////// Effects of interleukin 6 and tumor necrosis factor-α on the proliferation of porcine theca interna cells: Possible role of these cytokines in the pathogenesis of polycystic ovary syndrome. Hong L et al. (2016) We studied the effects of interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) on the proliferation of porcine theca interna (TI) cells and further elucidated the roles of IL-6 and TNF-α in the pathogenesis of polycystic ovary syndrome. TI cells were treated with 10 pg/mL, 100 pg/mL, and 1000 pg/mL IL-6 or TNF-α. TI cell proliferation was then examined by carboxyfluorescein diacetate succinimidyl ester labeling and flow cytometry. Cell proliferation was not significantly different in TI cells cultured in medium alone (control) or in the presence of IL-6. At 72 hours of treatment, the mean fluorescence intensity was significantly lower in TI cells treated with 100 pg/mL and 1000 pg/mL TNF-α than in the control (p < 0.05). TNF-α, but not IL-6, was able to promote TI cell proliferation. Our results suggest that TNF-α might play a role in hyperandrogenism, cortex thickness, and the increased ovary volume observed in polycystic ovaries.////////////////// Interleukin-6 up-regulates the expression of rat luteinizing hormone receptors during granulosa cell differentiation. Imai F 2014 et al. Interleukin-6 (IL-6) is produced in granulosa cells under normal physiological conditions, including during ovulation. However, the roles of IL-6 in ovarian function, including regulation of LH receptor (LHR) expression in granulosa cells, have not been explored in detail. The aim of this study was to identify the mechanism underlying the effect of IL-6 on LHR expression in the granulosa cells of female Wistar rats. Our results indicated that IL-6 clearly enhanced the FSH-induced LHR mRNA expression in a dose-dependent manner and did not stimulate cAMP accumulation by itself. The membrane protein level of LHR, assessed by a binding assay, was increased by FSH and was further enhanced by association with IL-6. Results of the luciferase assay, using promoter constructs of LHR 281 bp upstream of the translational start site, revealed that IL-6 increased promoter activity induced by FSH, but this effect was not observed with treatment by IL-6 alone. This ability of IL-6 to enhance FSH-induced LHR mRNA expression was blocked by the JAK pathway inhibitor, but not by the ERK1/2 inhibitor. Thus, we speculated that this IL-6 activity might be mediated by the JAK/STAT pathway. Additionally, IL-6 augmented FSH-induced IL-6Ra mRNA expression and FSH elevated IL-6 production in granulosa cells, which indicates that IL-6 may positively regulate paracrine and autocrine actions in granulosa cells. These results suggest that IL-6 up-regulates FSH-induced LHR production by increasing mRNA transcription, and JAK/STAT3 signaling is required for up-regulation by IL-6 in granulosa cells. ///////////////////////// IL-6 and mouse oocyte spindle. Banerjee J et al. Interleukin 6 (IL-6) is considered a major indicator of the acute-phase inflammatory response. Endometriosis and pelvic inflammation, diseases that manifest elevated levels of IL-6, are commonly associated with higher infertility. However, the mechanistic link between elevated levels of IL-6 and poor oocyte quality is still unclear. In this work, we explored the direct role of this cytokine as a possible mediator for impaired oocyte spindle and chromosomal structure, which is a critical hurdle in the management of infertility. Metaphase-II mouse oocytes were exposed to recombinant mouse IL-6 (50, 100 and 200 ng/mL) for 30 minutes and subjected to indirect immunofluorescent staining to identify alterations in the microtubule and chromosomal alignment compared to untreated controls. The deterioration in microtubule and chromosomal alignment were evaluated utilizing both fluorescence and confocal microscopy, and were quantitated with a previously reported scoring system. Our results showed that IL-6 caused a dose-dependent deterioration in microtubule and chromosomal alignment in the treated oocytes as compared to the untreated group. Indeed, IL-6 at a concentration as low as 50 ng/mL caused deterioration in the spindle structure in 60% of the oocytes, which increased significantly (P<0.0001) as IL-6 concentration was increased. In conclusion, elevated levels of IL-6 associated with endometriosis and pelvic inflammation may reduce the fertilizing capacity of human oocyte through a mechanism that involves impairment of the microtubule and chromosomal structure. IL6: an autocrine regulator of the mouse cumulus cell-oocyte complex expansion process. Liu Z et al. Ovulation has long been regarded as a process resembling an inflammatory response. Recent studies indicate that genes associated with innate immune responses were also expressed during the ovulation process. Because the innate immune genes are induced in cumulus cell oocyte complex (COCs) later than the inflammation-associated genes, we hypothesize that COC expansion is dependent on specific sequential changes in cumulus cells. Because interleukin 6 (IL6) is a potent mediator of immune responses, we sought to determine what factors regulate the induction of Il6 mRNA in COCs and what impact IL6 alone would have on COC expansion. We found that the levels of Il6 mRNA increased dramatically during COC expansion, both in vivo and in vitro. Moreover, IL6, together with its soluble receptor, IL6SR, could by-pass the need for either amphiregulin (AREG) and/or prostaglandin E2 (PGE2) to induce the expansion of COCs. This ability of IL6/IL6SR to induce COC expansion was blocked by the inhibitors to p38MAPK, MEK1/2 and Janus Kinase. More importantly, when COCs were in vitro maturated in the presence of IL6, they had a significantly higher embryo transfer rate than the ones without IL6 and comparable to in vivo matured oocytes. IL6/IL6SR activated multiple signaling pathways (JAK/STAT, ERK1/2, p38MAPK and AKT) and progressively induced genes known to impact COC expansion, genes related to inflammation and immune responses, and some transcription factors. Collectively, these data indicate that IL6 alone can act as a potent autocrine regulator of ovarian cumulus cell function, COC expansion and oocyte competence. Van der Hoek KH et al reported that preovulatory ovaries were taken from eCG-primed rat, and ovulation was induced by LH (100 ng/ml) alone or in combination with IL-6. Ovaries in the IL-6/LH groups did not have ovulation rates different from ovaries in the LH-only group. Although exogenous IL-6 did not significantly alter the LH-induced ovulation rate but significantly reduced the LH/IL-1beta-induced ovulation rate. In addition, exogenous IL-6 did not alter LH-induced progesterone levels measured at time points during the perfusion period, but the average increase in progesterone over basal level was stimulated by IL-6. Gorospe WC et al reported treatment of FSH-stimulated granulosa cells with increasing amounts of interleukin-6 (IL-6) caused a significant concentration-dependent suppression of progesterone biosynthesis. However, basal progesterone production in non-FSH-stimulated cells remained unresponsive to the cytokine. Quantitation of IL-6 in the conditioned media from untreated granulosa cells by the 7TD1 hybridoma cell bioassay revealed detectable levels of IL-6. Further, FSH treatment caused a concentration-dependent increase in IL-6 release. In contrast, both basal and FSH-stimulated IL-6 release could be significantly suppressed by interferon gamma (INF-gamma). Telleria CM et al studied the expression of interleukin-6 in the pregnant rat corpus luteum and its regulation by progesterone and glucocorticoid. Using semiquantitative RT-PCR, mRNA encoding both components of the IL-6 receptor the ligand-binding subunit (IL-6 R) and the IL-6 R-associated signal transducer (gp130) were found to be highly expressed in corpora lutea throughout pregnancy. In contrast, IL-6 mRNA expression was barely detectable from day 4 through the end of pregnancy, whereas a sharp and abrupt expression of IL-6 mRNA occurred immediately after parturition. Although the corpus luteum does not express IL-6 mRNA during most of pregnancy, it could be induced to express this gene with an in vivo injection of the bacterial endotoxin, lipopolysaccharide. Isolation of the small and large luteal cells by elutriation indicated that both cell populations can secrete IL-6 in culture. Sugino N et al reported that IL-6 induced a remarkable increase in Mn-SOD (superoxide dismutase) mRNA levels in both corpora lutea and a transformed luteal cell line but had no effect on Cu,Zn-SOD mRNA expression. Mn-SOD may play an important role in protecting luteal cells from inflammation-mediated oxidative damage. The Role of Interleukin-6 in the Regulation of Granulosa Cell Apoptosis during Follicular Atresia in Pig Ovaries. Maeda A et al. More than 99% of follicles in mammalian ovaries undergo a degenerative process known as atresia, and only a few follicles actually ovulate during follicular growth and development. Follicular selection mostly depends on granulosa cell apoptosis, but the molecular mechanism behind the regulation of this selective atresia is still largely unknown. In the present study, to examine whether or not interleukin-6 (IL-6), a multifunctional cytokine, is involved in apoptosis during atresia in pig ovaries, the expression of IL-6 mRNA in granulosa cells was quantified by real-time reverse transcription-polymerase chain reaction (RT-PCR). The level of mRNA decreased during atresia. Enzyme-linked immunosorbent assay (ELISA) showed that the level of IL-6 protein in follicular fluid also decreased during atresia. Moreover, recombinant human IL-6 upregulated the expression of an intracellular apoptosis inhibitor, cellular FLICE-like inhibitory protein long form (cFLIPL), in cultured cells derived from human granulosa cells. It is possible that IL-6 is produced in the granulosa cells of healthy follicles, that it increases the cFLIPL level, and cFLIPL then prevents apoptotic cell death. | ||||
| Expression regulated by | FSH, LH, Steroids, Growth Factors/ cytokines, IL6 | ||||
| Comment | Upregulation of the lncRNA SRLR in polycystic ovary syndrome regulates cell apoptosis and IL-6 expression. Li L et al. (2020) Increased levels of interleukin-6 (IL-6) contribute to the development of polycystic ovary syndrome (PCOS); in renal cell carcinoma, the long non-coding RNA (lncRNA) SRLR upregulates IL-6. In this study, we demonstrated that the levels of the lncRNA SRLR were upregulated in PCOS patients with high expression of plasma IL-6 compared with heathy females. The levels of the lncRNA SRLR in the plasma had a positive correlation with expression of IL-6 in patients with PCOS but not in healthy females. Upregulation of the lncRNA SRLR in plasma could distinguish PCOS patients from healthy females. Overexpression of the lncRNA SRLR led to upregulation of IL-6 and promoted apoptosis of human granulosa-like tumour cells (KGN). Therefore, the lncRNA SRLR participated in PCOS by regulating cell apoptosis and IL-6 expression. SIGNIFICANCE OF THE STUDY: The lncRNA SRLR mediates its effects on apoptosis and IL-6 expression in PCOS and could be used to distinguish PCOS patients from healthy controls. Plasma circulating levels of the lncRNA SRLR may be a potential target for the treatment of PCOS.////////////////// IL-1α Up-Regulates IL-6 Expression in Bovine Granulosa Cells via MAPKs and NF-κB Signaling Pathways. Yang M et al. (2017) IL-6 is one of the main cytokines in regulating ovarian follicular development and ovulation. However, the factors that regulate IL-6 expression in follicles are still unclear. The aim of this study was to elucidate the mechanisms underlying the effect of IL-1α on IL-6 expression in granulosa cells. IL-6 expression after IL-1α with/without inhibitors treatment was analyzed by RT-qPCR and ELISA. The phosphorylation of proteins induced by IL-1α was analyzed by western blot. The intracellular cAMP level was assayed by immunoassay kit. IL-1α has a dose-dependent effect on IL-6 expression in granulosa cells. This promoting effect can be significantly attenuated by Erk, c-Jun, p38 and IκB proteins inhibitors, respectively. Moreover, the phosphorylation levels of Erk, c-Jun, p38 and IκBα proteins were significantly increased after IL-1α treatment. In addition, we also found that IL-1α not only reversed the cAMP attenuated IL-6 expression， but also increased IL-1α mRNA expression in granulosa cells. The regulation of IL-1α on IL-6 expression is mediated by activation of MAPKs and NF-κB signaling pathways. Moreover，IL-1α may regulate the ovulation-related genes expression in granulosa cells by an autocrine and/or paracrine manner.////////////////// Pathogen-associated molecular patterns initiate inflammation and perturb the endocrine function of bovine granulosa cells from ovarian dominant follicles via TLR2 and TLR4 pathways. Price JC 2013 et al. Bacterial infections of the uterus or mammary gland commonly cause disease and infertility by perturbing growth and steroidogenesis of the dominant follicle in the ovary of cattle. Cells of the innate immune system use Toll-like receptors TLR2, TLR4 and TLR5 to recognize pathogen-associated molecular patterns (PAMPs) expressed by bacteria, leading to activation of MAPK and NF?B pathways, and production of inflammatory cytokines such as IL-1?and IL-6, and the chemokine IL-8. The present study tested whether granulosa cells from dominant follicles have functional TLR2, TLR4 and TLR5 pathways. Supernatants of primary bovine granulosa cells accumulated IL-1? IL-6 and IL-8 when treated for 24 h with PAM that binds TLR2 or LPS that binds TLR4, but not flagellin that binds TLR5. Granulosa cell responses to PAM or LPS were rapid, with increased phosphorylation of p38 and ERK1/2 within 30 min and increased abundance of IL6, IL1B, IL10, TNF, IL8 and CCL5 mRNA after 3 h treatment. Accumulation of IL-6 in response to PAM and LPS was attenuated using siRNA targeting TLR2 and TLR4, respectively. Furthermore, treating granulosa cells with inhibitors targeting MAPK or NF?B reduced the accumulation of IL-6 in response to LPS or PAM. Treatment with LPS or PAM reduced the accumulation of estradiol and progesterone, and the PAMPs reduced granulosa cell expression of CYP19A1 mRNA and protein. In conclusion, bacterial PAMPs initiate inflammation and perturb the endocrine function of bovine granulosa cells from dominant follicles via TLR2 and TLR4 pathways.Pr?s: A rapid inflammatory response to pathogen-associated molecular patterns mediated by TLR2 and TLR4 pathways in granulosa cells provides a molecular explanation of how bacterial infections distant to the ovary can perturb dominant follicle function. ///////////////////////// Lipopolysaccharide Initiates Inflammation in Bovine Granulosa Cells via the TLR4 Pathway and Perturbs Oocyte Meiotic Progression in Vitro. Bromfield JJ et al. Infections of the reproductive tract or mammary gland with Gram-negative bacteria perturb ovarian function, follicular growth, and fecundity in cattle. We hypothesized that lipopolysaccharide (LPS) from Gram-negative bacteria stimulates an inflammatory response by ovarian granulosa cells that is mediated by Toll-like receptor (TLR) 4. The present study tested the capacity of bovine ovarian granulosa cells to initiate an inflammatory response to pathogen-associated molecular patterns and determined subsequent effects on the in vitro maturation of oocytes. Granulosa cells elicited an inflammatory response to pathogen-associated molecular patterns (LPS, lipoteichoic acid, peptidoglycan, or Pam3CSK4) with accumulation of the cytokine IL-6, and the chemokine IL-8, in a time- and dose-dependent manner. Granulosa cells responded acutely to LPS with rapid phosphorylation of TLR signaling components, p38 and ERK, and increased expression of IL6 and IL8 mRNA, although nuclear translocation of p65 was not evident. Targeting TLR4 with small interfering RNA attenuated granulosa cell accumulation of IL-6 in response to LPS. Endocrine function of granulosa cells is regulated by FSH, but here, FSH also enhanced responsiveness to LPS, increasing IL-6 and IL-8 accumulation. Furthermore, LPS stimulated IL-6 secretion and expansion by cumulus-oocyte complexes and increased rates of meiotic arrest and germinal vesicle breakdown failure. In conclusion, bovine granulosa cells initiate an innate immune response to LPS via the TLR4 pathway, leading to inflammation and to perturbation of meiotic competence. Machelon V et al reported that IL-6 is produced by human granulosa cells in the preovulatory follicle at the time of ovulation. In addition, IL-6 might be an intraovarian regulatory factor concerned with steroidogenesis. Gorospe WC et al showed that the rat granulosa cell is not only a source of IL-6 but that the release of IL-6 can be regulated. Moreover, evidence suggests that cAMP may serve as a second messenger for the stimulated secretion of IL-6 by undifferentiated granulosa cells. Telleria CM et al cultured corpora lutea from day-15 pregnant rats were cultured in the presence of different doses of progesterone; the synthetic glucocorticoid, dexamethasone; 17beta-estradiol; and PRL. Progesterone and dexamethasone markedly inhibited IL-6 mRNA expression, whereas 17beta-estradiol had a minimal inhibitory effect, and PRL did not affect IL-6 mRNA expression. Loret de Mola JR et al reported that gonadotropins induce the release of interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha from the human preovulatory follicle. Machelon V, et al. reported that tumor necrosis factor-alpha induces interleukin-6 mRNA and protein in human granulosa luteinizing cells via protein tyrosine kinase without involving ceramide. | ||||
| Ovarian localization | Primordial Germ Cell, Granulosa, Luteal cells, Small luteal cells, Large luteal cells, Follicular Fluid | ||||
| Comment | Follicular-phase ovarian follicular fluid and plasma cytokine profiling ofnatural cycle invitro fertilization patients. Baskind NE 2014 et al. OBJECTIVE To characterize follicular fluid (FF) and systemic cytokine profiles at various time points during the natural-cycle follicular and periovulatory phases. DESIGN Observational clinical study across two consecutive cycles. SETTING Hospital-basedin vitro fertilization program. PATIENT(S) Ten women undergoing modified natural-cycle invitro fertilization (MNC-IVF). INTERVENTION(S) Plasma and follicular fluid (FF) collection. MAIN OUTCOME MEASURE(S) Forty FF cytokine concentrations from individual follicles and plasma from each patient were determined by fluid-phase multiplex immunoassay in two consecutive cycles: 1) tracking cycle-midfollicular or luteal surge; and 2) treatment cycle-periovulatory (at the time of MNC-IVF). Demographic, cycle, and cytokine data were compared with the use of chi-square, paired-scores t test, or Wilcoxon signed ranks tests. RESULT(S) Fluctuations in various FF cytokines were evident during the follicular phase: Levels of interleukin (IL) 6 and IL-8 were higher in periovulatory samples, and IL-1 receptor antagonist and vascular endothelial growth factor were elevated earlier in the cycle. Luteal surge profiles were similar to those found in periovulatory samples. Conversely, circulatory cytokine concentrations were more stable during the follicular phase. CONCLUSION(S) These findings present an extensive physiologic reference profile of FF cytokines associated with antral folliculogenesis and highlight the compartmentalization of systemic and intraovarian cytokine networks in natural cycles. ///////////////////////// Developmentally-regulated IL6-type cytokines signal to germ cells in the human fetal ovary. Eddie SL et al. Fetal ovarian development and primordial follicle formation are imperative for adult fertility in the female. Data suggest the interleukin (IL)6-type cytokines, leukemia inhibitory factor (LIF), IL6, oncostatin M (OSM) and cilary neurotrophic factor (CNTF), are able to regulate the survival, proliferation and differentiation of fetal murine germ cells (GC) in vivo and in vitro. We postulated that these factors may play a similar role during early human GC development and primordial follicle formation. To test this hypothesis, we have investigated the expression and regulation of IL6-type cytokines, using qRT-PCR and immunohistochemistry. Expression of transcripts encoding OSM increased significantly across the gestational range examined (8-20 weeks), whilst expression of IL6 increased specifically between the first (8-11 weeks) early second (12-16 weeks) trimesters, co-incident with the initiation of meiosis. LIF and CNTF expression remained unchanged. Expression of the genes encoding the LIF and IL6 receptors, and their common signalling subunit gp130, were also found to be developmentally-regulated, with expression increasing significantly with increasing gestation. LIFR and gp130 proteins localised exclusively to GCs, including oocytes in primordial follicles, indicating this cell type to be the sole target of IL6-type cytokine signalling in the human fetal ovary. These data establish that IL6-type cytokines and their receptors are expressed in the human fetal ovary, and may directly influence germ cell development at multiple stages of maturation. Calogero AE, et al. reported elevated levels of interleukin 6 and low levels of granulocyte-macrophage colony-stimulating factor in the follicular fluids of women with infertility due to immunological causes. Keck C et al reported the expression of interleukin-6 and interleukin-6 receptors in human granulosa lutein cells. | ||||
| Follicle stages | Antral, Preovulatory, Corpus luteum | ||||
| Comment | Salivary Interleukin-6 Levels among Polycystic Ovary Syndrome Patients with and Without Chronic Periodontitis - A Comparative Study. Varghese A et al. (2020) Periodontitis is associated with various systemic diseases one of which is poly cystic ovarian syndrome (PCOS). PCOS is a genetically complex endocrinopathy of uncertain etiology affecting women of the reproductive age group which results in the most common cause of anovulatory infertility, menstrual dysfunction, and hirsutism. PCOS has a close association with cardiometabolic risk profile, insulin resistance (IR), hyperinsulinemia, central obesity, dyslipidemia, and increasing the prevalence of cardiovascular risk factors. The common pathway is the chronic low-grade inflammation which is constituted by pro-inflammatory cytokine interleukin (IL)-6. The aim of the study was to compare salivary IL-6 levels among polycystic ovary syndrome (PCOS) patients with and without chronic periodontitis. Newly diagnosed PCOS patients were selected for the study, and the periodontal parameters were recorded. Group A consists of 42 patients of PCOS with periodontitis and Group B consists of 42 patients of PCOS without periodontitis. Salivary levels of IL-6 were compared between the two groups and were assessed by enzyme-linked immunosorbent assay kit (bioassay). The mean pocket depth in Group A was 4.23 ± 0.134 and that of Group B was 1.30 ± 0.06. The mean bleeding on probing in Group A was 1.40 ± 0.40 and in Group B it was 0.91 ± 0.18. The mean clinical attachment level in Group A was 4.87 ± 0.124 and that of Group B was 1.30 ± 0.06. The mean difference in clinical parameters was statistically significant between the groups (P ≤ 0.001). IL-6 level in group A is 102.59 ± 18.2 and in Group B it was 51.3 ± 25.3. Salivary IL-6 levels show a double-fold increase in PCOS with periodontitis than in PCOS without periodontitis. This study reflects the importance of periodontal health and the prevention of periodontal disease so as to minimize IR in PCOS patients with periodontitis.//////////////////Age-associated changes in granulosa cell transcript abundance in equine preovulatory follicles. Sessions-Bresnahan DR et al. (2015) Age-related changes in follicle paracrine signalling are not defined, and follicular gene transcript abundance could predict oocyte viability. Granulosa cells from preovulatory follicles of mares considered Young (n=12; 4-14 years), Mid-aged (n=9; 15-19 years) and Old (n=14; 20-27 years) were evaluated for transcript abundance related to systemic and follicle-specific pathways. Gene transcript abundance for receptors of insulin, adiponectin and peroxisome proliferating factor-? were higher or tended to be higher in Mid-aged or Old than Young mares. Transcript abundance for interleukin (IL)-6 was elevated in Old versus Young mares, and IL-6 signal transducer was elevated in Old versus younger groups. Expression of tumour necrosis factor (TNF) receptor superfamily member 1A was higher in Mid-aged than Young mares, whereas TNF-inducible gene 6 protein mRNA tended to decrease in Mid-aged versus Young and Old mares. Genes for LH receptor and steroidogenic acute regulatory protein tended to be increased in Old versus Mid-aged and Young mares, respectively. Young and Old mares had higher mRNA for tissue-type plasminogen activator than Mid-aged mares. Thioredoxin-2 mRNA was higher in Old than younger groups. We observed age-related changes in mRNA of receptors for metabolic hormones, inflammatory processes, steroidogenic hormones, tissue remodelling and mitochondrial function, which could contribute to and/or mark alterations in follicular function and fertility.////////////////// | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
10 mutations
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Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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