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Interleukin-6 deficiency modulates testicular function by increasing the expression of suppressor of cytokine signaling 3 (SOCS3) in mice.

ABSTRACT: Several cytokines have been reported to participate in spermatogenesis, including interleukin-6 (IL6). However, not many studies have been conducted on the loss of Il6 on the male reproductive tract. Nonetheless, there is considerable knowledge regarding the pathological and physiological role of IL6 on spermatogenesis. In this way, this study evaluated the impact of Il6 deficiency on mice testicles in the absence of infection or inflammation. We showed that Il6 deficiency increases daily sperm production, the number of spermatids, and the testicular testosterone and dihydrotestosterone levels. Besides that, mice with a deleted Il6 (IL6KO) showed increased testicular SOCS3 levels, with no changes in pJAK/JAK and pSTAT3/STAT3 ratios. It is worth noting that the aforementioned pathway is not the only pathway to up-regulate SOCS3, nor is it the only SOCS3 target, thus proposing that the increase of SOCS3 in the testis occurs independently of the JAK-STAT signaling in IL6KO mice. Therefore, we suggest that the lack of Il6 drives androgenic production by increasing SOCS3 in the testis, thus leading to an increase in spermatogenesis.

SUBMITTER: Alves-Silva T

PROVIDER: S-EPMC8169872 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Prerequisites for Functional Interleukin 31 Signaling and Its Feedback Regulation by Suppressor of Cytokine Signaling 3 (SOCS3).

Project description:Interleukin-31 (IL-31) is a T helper type 2 cell-derived cytokine tightly associated with inflammatory skin disorders. IL-31-induced signaling is mediated by a receptor complex composed of oncostatin M receptor β and the cytokine-specific receptor subunit IL-31Rα, of which there are several isoforms. The latter can be classified as long or short isoforms with respect to their intracellular domain. At present, the signaling capabilities of the different isoforms remain inchoately understood, and potential mechanisms involved in negative regulation of IL-31Rα signaling have so far not been studied in detail. Here, we show that both the long and short isoforms of IL-31Rα are capable of inducing STAT signaling. However, the presence of a functional JAK-binding box within IL-31Rα is an essential prerequisite for functional IL-31-mediated STAT3 signaling. Moreover, both the long and short isoforms require oncostatin M receptor β for their activity. We also show that IL-31 induces expression of four suppressor of cytokine signaling family members and provide evidence that SOCS3 acts as a potent feedback inhibitor of IL-31-induced signaling. Taken together, this study identifies crucial requirements for IL-31 signaling and shows its counter-regulation by SOCS3.

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Expression of suppressor of cytokine signaling 3 (SOCS3) and interleukin-6 (-174-G/C) polymorphism in atopic conditions.

Project description:Hypersensitivity of the immune system is caused by elevated immunoglobulin E (IgE) levels in the serum, in response to a discrete allergen leading to allergic reactions. IgE-mediated inflammation is regulated by the cascade of defense related signaling molecules including interleukin-6 (IL-6) that plays pivotal role in the survival and maturation of mast cells during an allergic reaction. IL-6 mediated defense responses are tightly regulated by Suppressor of Cytokine Signaling 3 (SOCS3), an inhibitory molecules of Janus Kinase-Signal Transducers and Activators of Transcription (JAK-STAT) signaling, in a negative feedback mechanism. The given study focuses on the assessment of crosstalk between SOCS3 and IL-6 to unravel the molecular significance of SOCS3 and IL-6 in the diagnosis and prognosis of allergy. The expression study of SOCS3 through real-time PCR analysis revealed, a 5.9 mean fold increase in SOCS3 expression in atopic cases in comparison to control cases. Moreover, IL-6 has, also, been found significantly enhanced in the serum level of atopic cases (26.4 pg/ml) as compared to control cases (3.686 pg/ml). Female population was found to be at a higher risk to develop atopic condition than male population as females exhibited higher expression of both SOCS3 and IL-6 than males. Furthermore, the polymorphic study of IL-6 promoter region (IL-6 174-G/C) in atopic population has reasserted the importance of SOCS3 and IL-6 in the diagnosis and prognosis of allergy. Expression of SOCS3 and IL-6 serum levels were found to be highly correlated. Therefore establishing the role of IL-6 (-174-G/C) polymorphism on the expression of SOCS3 and IL-6 in atopic cases. Notably, the study established SOCS3 and IL-6 as potential targets for the diagnosis/prognosis of allergy and for the development of reliable therapeutic strategies to control atopic conditions in the near future.

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Project description:Effective suppression of JAK-STAT signalling by the inducible inhibitor "suppressor of cytokine signalling 3" (SOCS3) is essential for limiting signalling from cytokine receptors. Here we show that cavin-1, a component of caveolae, is a functionally significant SOCS3-interacting protein. Biochemical and confocal imaging demonstrate that SOCS3 localisation to the plasma membrane requires cavin-1. SOCS3 is also critical for cavin-1 stabilisation, such that deletion of SOCS3 reduces the expression of cavin-1 and caveolin-1 proteins, thereby reducing caveola abundance in endothelial cells. Moreover, the interaction of cavin-1 and SOCS3 is essential for SOCS3 function, as loss of cavin-1 enhances cytokine-stimulated STAT3 phosphorylation and abolishes SOCS3-dependent inhibition of IL-6 signalling by cyclic AMP. Together, these findings reveal a new functionally important mechanism linking SOCS3-mediated inhibition of cytokine signalling to localisation at the plasma membrane via interaction with and stabilisation of cavin-1.

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Suppressor of Cytokine Signaling 3 (SOCS3) Degrades p65 and Regulate HIV-1 Replication.

Project description:Human Immunodeficiency Virus-1 (HIV-1) is known to induce the expression of SOCS3 which is a negative feed-back regulator of inflammatory responses. Here, we demonstrate that reactivation of latent HIV-1 leads to degradation of SOCS3 at early time points. Interestingly, SOCS3 degradation following transfection of HIV-1 RNA as well as polyIC in THP-1 cells further confirmed the role of viral RNA signaling in SOCS3 biology. Degradation of SOCS3 contributes toward viral RNA induced inflammatory responses. NF-κB signaling is also induced upon HIV-1 infection which leads to the production of pro-inflammatory cytokines to control the viral spread. Further investigations revealed that SOCS3 inhibits the expression and activity of p65 by interacting with it and inducing its ubiquitin-dependent proteasomal degradation. SH2 domain was critical for SOCS3-p65 interaction and p65 degradation. We also found that expression of SOCS3 promotes HIV-1 replication. Thus, HIV-1 downregulates SOCS3 in early phase of infection to promote inflammatory responses for large production of activated cells which are suitable for viral spread and induces SOCS3 later on to limit inflammatory responses and ensure viral survival.

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Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis.

Project description:A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR), is responsible for controlling the balance between pro-inflammatory interleukin (IL)-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR)-activation and glucose-deprivation or co-treatment with 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG) increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation.

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Regulation of insulin and leptin signaling by muscle suppressor of cytokine signaling 3 (SOCS3).

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Deletion of suppressor of cytokine signaling 3 (SOCS3) in muscle stem cells does not alter muscle regeneration in mice after injury.

Project description:Muscles of older animals are more susceptible to injury and regenerate poorly, in part due to a persistent inflammatory response. The janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway mediates inflammatory signaling and is tightly regulated by the suppressor of cytokine signaling (SOCS) proteins, especially SOCS3. SOCS3 expression is altered in the muscle of aged animals and may contribute to the persistent inflammation and impaired regeneration. To test this hypothesis, we performed myotoxic injuries on mice with a tamoxifen-inducible deletion of SOCS3 specifically within the muscle stem cell compartment. Muscle stem cell-specific SOCS3 deletion reduced muscle mass at 14 days post-injury (-14%, P < 0.01), altered the myogenic transcriptional program, and reduced myogenic fusion based on the number of centrally-located nuclei per muscle fiber. Despite the delay in myogenesis, muscles with a muscle stem cell-specific deletion of SOCS3 were still able to regenerate after a single bout or multiple bouts of myotoxic injury. A reduction in SOCS3 expression in muscle stem cells is unlikely to be responsible for the incomplete muscle repair in aged animals.

| S-EPMC6392323 | biostudies-literature

IFNg-/- and conditional Socs3-/- mice: cytokine treatments

Project description:Changes in mouse liver mRNA profiles following intraperitoneal cytokine injection. Either interferon-gamma-/-, albumin-cre(-) Socs3(w/fl) mice, or albumin-cre(+) Socs3(-/fl) mice were injected with either phosphate-buffered saline, interferon-gamma, or interfeukin-6, and livers taken after 4h. Keywords = Socs3, interferon gamma, interleukin-6, il6, liver, suppressor of cytokine signalling 3 Keywords: repeat sample

2003-04-10 | GSE369 | GEO

DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood.

Project description:Human height is strongly influenced by genetics but the contribution of modifiable epigenetic factors is under-explored, particularly in low and middle-income countries (LMIC). We investigate links between blood DNA methylation and child height in four LMIC cohorts (n = 1927) and identify a robust association at three CpGs in the suppressor of cytokine signaling 3 (SOCS3) gene which replicates in a high-income country cohort (n = 879). SOCS3 methylation (SOCS3m)-height associations are independent of genetic effects. Mendelian randomization analysis confirms a causal effect of SOCS3m on height. In longitudinal analysis, SOCS3m explains a maximum 9.5% of height variance in mid-childhood while the variance explained by height polygenic risk score increases from birth to 21 years. Children's SOCS3m is associated with prenatal maternal folate and socio-economic status. In-vitro characterization confirms a regulatory effect of SOCS3m on gene expression. Our findings suggest epigenetic modifications may play an important role in driving child height in LMIC.

| S-EPMC10457295 | biostudies-literature

Ascorbate protects liver from metabolic disorder through inhibition of lipogenesis and suppressor of cytokine signaling 3 (SOCS3).

Project description:Background:Fatty liver is a reversible status, but also an origin stage to develop to other metabolic syndromes, such as diabetes and heart disease that threatens public health worldwide. Ascorbate deficiency is reported to be correlated with increasing risks for metabolic syndromes, but whether ascorbate has a therapeutic effect is unknown. Here, we investigated if ascorbate treatment alone could work on protecting from the development of steatosis and mechanisms beyond. Methods:Guinea pigs were fed with a chow diet or a high palm oil diet (HPD) respectively. HPD induced animals were administered different concentrations of ascorbate in different time intervals through water. Besides, hepatocyte-like cells derived from human embryonic stem cells and HepG2 cells were treated with palmitic acid (PA) to induce lipid accumulation for molecular mechanism study. Results:We find that ascorbate rescues HPD and PA induced steatosis and insulin tolerance in vivo and in vitro. We demonstrate that ascorbate changes cellular lipid profiles via inhibits lipogenesis, and inhibits the expression of SOCS3 via STAT3, thus enhances insulin signal transduction. Overexpression of SOCS3 abolishes the ascorbate rescue effects on insulin signal and lipid accumulation in hepatic cells. Conclusions:Ascorbate ameliorates hepatic steatosis and improves insulin sensitivity through inhibiting lipogenesis and SOCS3.

| S-EPMC7057613 | biostudies-literature

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