Interleukin-6 (IL6; 147620) is a multifunctional cytokine that is essential to the regulation of the immune response, hematopoiesis, and acute-phase reactions. It exerts its many actions through a heterodimeric receptor consisting of 2 membrane-bound glycoproteins: an 80-kD IL6-binding subunit, IL6R-alpha, and gp130 (IL6ST; 600694), which is responsible for signal transduction and stabilization of the alpha-chain ligand complex.
NCBI Summary:
Interleukin 6 (IL6) is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in immune response. The protein encoded by this gene is a subunit of the receptor complex for IL6. The IL6 receptor is a protein complex consisting of this protein and interleukin 6 signal transducer (IL6ST/GP130/IL6-beta), a receptor subunit also shared by many other cytokines. Dysregulated production of IL6 and this receptor are implicated in the pathogenesis of many diseases, such as multiple myeloma, autoimmune diseases and prostate cancer. Alternatively spliced transcript variants encoding distinct isoforms have been reported.
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.
Tamura K, et al. ( Mol Cell Endocrinol. 2000)found that treatment of GC cells with IL-6 for 72 h during the process of in vitro GC maturation dose-dependently inhibited the accumulation of estradiol-17beta (E(2)) and the expression of cytochrome P450 aromatase (P450arom). IL-6 did not change nitric oxide (NO) production and inducible NO synthase expression, implying that IL-6-induced suppression on E(2) levels is dissociated with NO expression.
Expression regulated by
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Ovarian localization
Granulosa
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Tamura K, et al. ( Mol Cell Endocrinol. 2000)revealed that IL-6R exists in GC cells by reverse transcription-polymerase chain reaction (RT-PCR) analysis.
Changes in Expression of Interleukin-6 Receptors in Granulosa Cells During Follicular Atresia in Pig Ovaries. Maeda A et al. More than 99% of follicles undergo a degenerative process known as atresia in mammalian ovaries, and only a few follicles ovulate during follicular growth and development. Follicular selection predominantly depends on granulosa cell apoptosis. To reveal the molecular mechanisms of selective follicular atresia, we examined the changes in the levels of interleukin-6 (IL-6) receptors expressed in the granulosa cells of pig ovaries. The levels of IL-6 receptor (IL-6R) alpha mRNA and protein in granulosa cells were quantified by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. IL-6Ralpha mRNA and protein were highly expressed in the granulosa cells of progressed atretic follicles. Enzyme-linked immunosorbent assay (ELISA) showed that the expression of IL-6 soluble receptor (IL-6sR) protein in follicular fluid decreased during atresia. Moreover, we isolated porcine cDNA encoding an IL-6 signal transducer, gp130. Porcine gp130 (2754 bp and 917-aa) was identified from a cDNA library prepared using follicular granulosa cells of pig ovaries. Porcine gp130 was highly homologous with human and murine gp130. RT-PCR analysis revealed that the level of gp130 mRNA also decreased during atresia. We presume that IL-6sR and gp130, but not IL-6Ralpha, play important roles in regulation of granulosa cell survival.