Role Of SOCS3 Research Articles

The Role of SOCS3 in Regulating Meat Quality in Jinhua Pigs

Meat quality is an important economic trait that influences the development of the pig industry. Skeletal muscle development and glycolytic potential (GP) are two crucial aspects that significantly impact meat quality. It has been reported that abnormal skeletal muscle development and high glycogen content results in low meat quality. However, the genetic mechanisms underlying these factors are still unclear. Compared with intensive pig breeds, Chinese indigenous pig breeds, such as the Jinhua pig, express superior meat quality characteristics. The differences in the meat quality traits between Jinhua and intensive pig breeds make them suitable for uncovering the genetic mechanisms that regulate meat quality traits. In this study, the Jinhua pig breed and five intensive pig breeds, including Duroc, Landrace, Yorkshire, Berkshire, and Pietrain pig breeds, were selected as experimental materials. First, the FST and XP-EHH methods were used to screen the selective signatures on the genome in the Jinhua population. Then, combined with RNA-Seq data, the study further confirmed that SOCS3 could be a key candidate gene that influences meat quality by mediating myoblast proliferation and glycometabolism because of the down-regulated expression of SOCS3 in Jinhua pigs compared with Landrace pigs. Finally, through SOCS3 knockout (KO) and overexpression (OE) experiments in mouse C2C12 cells, the results showed that SOCS3 regulated the cell proliferation of myoblasts. Moreover, SOCS3 is involved in regulating glucose uptake by the IRS1/PI3K/AKT signaling pathway. Overall, these findings provide a basis for the genetic improvement of meat quality traits in the pig industry.

IL-17A Mediates Demyelination by Activating A1 Astrocytes via SOCS3 During Angiostrongylus cantonensis Infection.

BackgroundDemyelinating disease of the central nervous system is one of the most common neurological diseases and effective treatment is still under in-depth research. Our previous study showed that Angiostrongylus cantonensis infection can induce demyelination injury in mouse brains and IL-17A expression was shown to be significantly increased during this process. Moreover, we found that IL-17A inhibition attenuated the demyelination caused by A. cantonensis infection. However, the underlying mechanisms have not yet been fully elucidated.MethodsIL-17A neutralizing antibodies were injected into A. cantonensis infected mice to decrease IL-17A levels. The activation of glial cells in the brain and the expression of cell markers were detected by a variety of methods, including real-time quantitative PCR, western blotting, and immunofluorescence staining. The relationship between IL-17A and astrocyte activation was further identified by in vitro experiments. The role of SOCS3 in the IL-17A stimulating process was determined using RNA-seq data collection of infected mice and the siRNA interference method.ResultsDemyelination of the corpus callosum was relieved after administration of IL-17A neutralizing antibody and this was accompanied by decreased activation of A1 type astrocytes around this region. The expression of SOCS3 was attenuated and activation of astrocytes by IL-17A was mediated by the IL-17RA/STAT3/SOCS3 pathway. IL-17A not only directly damaged oligodendrocytes but also indirectly damaged oligodendrocytes through A1 astrocyte mediation. Specific siRNA inhibition of IL-17A-inducible SOCS3 in astrocytes alleviated their damaging effects on oligodendrocytes.ConclusionIL-17A plays an important role in demyelination induced by A. cantonensis infection via the IL-17RA/STAT3/SOCS3 pathway in A1-type astrocytes, indicating that specific blockage of IL-17A and SOCS3 activity could be a therapeutic strategy for neuroinflammatory demyelinating diseases associated with astrocyte activation.

Smooth muscle cell-specific SOCS3 deficiency promote pericardial fibrosis and diastolic dysfunction in aging mice

Abstract Background Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible negative regulator of signal transducer and activator of transcription-3 (STAT3) signaling pathway. We have previously shown that cardiac-specific SOCS3 deficiency spontaneously develop cardiac dysfunction with advanced age. However, the role of SOCS3 in smooth muscle cells in cardiovascular pathophysiology remains elusive. In this study, we determined whether STAT3 and SOCS3 in smooth muscle cells would play a role in cardiovascular pathophysiology. Methods and results To target inactivation of the SOCS3 gene to smooth muscle cells, SOCS3-flox mice were bred with transgenic mice expressing Cre recombinase under control of the mouse SM22-α promoter (sm-SOCS3-KO mice). Left ventricular weight to body weight ratio was significantly increased in sm-SOCS3-KO mice compared with wild-type mice at 12 months of age (p<0.05). Echocardiographic analyses of smSOCS3-KO mice showed significantly increased left ventricular diastolic dysfunction compared with wild-type from 12 months of age (p<0.05). Sirius-red staining revealed that thickness of pericardium and cardiac interstitial fibrosis in sm-SOCS3-KO mice were markedly greater compared with wild-type mice at 12 months of age (p<0.05). Western blot analyses showed that phosphorylated STAT3 was significantly increased in sm-SOCS3-KO hearts compared with wild-type mice at 12 months of age (p<0.05), whereas no significant differences were observed at 2 months of age. To investigate the mechanism that gave rise to promoted cardiac fibrosis and diastolic dysfunction during aging in sm-SOCS3-KO, we conducted a real-time PCR array analysis for fibrosis. The expression of pro-fibrotic CTGF (connective tissue growth factor), PDGFb (platelet growth factor-b), and TGF (transforming growth factor) family genes including TGFb1, TGFb2, and TGFb3, were significantly higher in sm-SOCS3-KO hearts than those in wild-type at 6 months of age. Conclusion Thus, smooth muscle cell-specific SOCS3 deletion induces increased pericardial fibrosis, cardiac interstitial fibrosis, and increased diastolic dysfunction in aging mice, possibly through the augmentation of pro-fibrotic growth factors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant JSPS KAKENHI

Study of Expression of Suppressor of Cytokine Signaling 3 in Lichen Planus

Background: Lichen planus (LP) is a mucocutaneous disease that is relatively common between adult populations. LP can present as skin and oral lesions. Objective: The present study aimed to detect the expression of SOCS3 in lichen planus of diseased patients as compared to normal control persons. Patients and methods: This study was a case control study included 30 Lichen planus patients as cases chosen from outpatients attending Dermatology Department at Beni- Suef University Hospital and 30 normal as controls calculated by sample size calculator formula. Results: In our study, LP cases and control were compared using SOCS3; to determine the cut-off value, we performed a ROC analysis. SOCS3 has perfect value for discrimination between LP cases and controls with an area under the ROC curve of 1.0 (95% CI = 0.940 to 1.000, P-value <0.0001). Best cut-off is a value of 1.5 (sensitivity = 100%, specificity = 1.0, J-index = 1.0). Conclusion: Our results were unique in studying the role of SOCS3 in skin form of LP. SOCS3 has perfect value for discrimination between LP cases and controls.

SOCS3 Attenuates GM-CSF/IFN-\u03b3-Mediated Inflammation During Spontaneous Spinal Cord Regeneration

SOCS3, a feedback inhibitor of the JAK/STAT signal pathway, negatively regulates axonal regrowth and inflammation in the central nervous system (CNS). Here, we demonstrated a distinct role of SOCS3 in the injured spinal cord of the gecko following tail amputation. Severing the gecko spinal cord did not evoke an inflammatory cascade except for an injury-stimulated elevation of the granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN-γ) cytokines. Simultaneously, the expression of SOCS3 was upregulated in microglia, and unexpectedly not in neurons. Enforced expression of SOCS3 was sufficient to suppress the GM-CSF/IFN-γ-driven inflammatory responses through its KIR domain by attenuating the activities of JAK1 and JAK2. SOCS3 was also linked to GM-CSF/IFN-γ-induced cross-tolerance. Transfection of adenovirus overexpressing SOCS3 in the injured cord resulted in a significant decrease of inflammatory cytokines. These results reveal a distinct role of SOCS3 in the regenerating spinal cord, and provide new hints for CNS repair in mammals.

P1627Increased pericardial fibrosis and cardiac dysfunction in smooth muscle cell-specific SOCS3 deficient mice

Abstract Background Suppressor of cytokine signaling-3 (SOCS3) is an intrinsic negative-feedback regulator of signal transducer and activator of transcription-3 (STAT3) signaling pathway. We have previously shown that myocardial SOCS3 plays an important role in cardiac hypertrophy and survival; however, the role of SOCS3 in smooth muscle cells in cardiovascular pathophysiology remains elusive. In this study, we determined whether STAT3 and SOCS3 in smooth muscle cells would play a role in cardiovascular pathophysiology. Methods and results To target inactivation of the SOCS3 gene to smooth muscle cells, SOCS3-flox mice were bred with transgenic mice expressing Cre recombinase under control of the mouse SM22-α promoter (sm-SOCS3-KO mice). Left ventricular weight to body weight ratio was significantly increased in sm-SOCS3-KO mice compared with wild-type mice at 52 weeks of age (p&lt;0.05). Echocardiographic analyses of sm-SOCS3-KOmice showed significantly decreased cardiac function compared with wild-typefrom 52 weeks of age (p&lt;0.05). Interestingly, Sirius-red staining revealed that thickness of pericardium in sm-SOCS3-KOmice was markedly greater compared with wild-typemice at 52 weeks of age (p&lt;0.05). Cardiac interstitial fibrosis in sm-SOCS3-KOmice was also greater compared with wild-typemice (p&lt;0.05). Western blot analyses showed that phosphorylated STAT3 was significantly increased in sm-SOCS3-KOhearts compared with wild-typemice at 52 weeks of age (p&lt;0.05), whereas no significant differences were observed at 7 weeks of age. Immunostaining revealed that phosphorylated STAT3 positive cells were in thickened pericardial area in sm-SOCS3-KOhearts. Some infiltrated inflammatory cells were also found in thickened pericardial area in sm-SOCS3-KOmice hearts. Conclusion These results suggest that STAT3 and its negative-feedback regulator SOCS3 in smooth muscle cells play an important role in the pathogenesis of pericardial fibrosis and cardiac dysfunction.

Role of SOCS3 in enhanced acute-phase protein genes by neonatal macrophages in response to IL-6.

Interleukin 6 (IL-6) induce the inflammatory response directly related with the morbidity and mortality of neonatal. Here we aimed to explore the mechanism of IL-6 in neonatal inflammatory response by studying the IL-6/STAT3 signaling pathway. Cord blood samples from health term neonatal and peripheral venous blood from health volunteers were collected. The monocytes of adults and cord blood were isolated and induced into macrophages. Then the macrophages were pretreated with or without MG132 before IL-6 stimulation. Proteins were analyzed by Western blot, mRNA by real time PCR and membrane molecule by flow cytometry. The acute phase protein gene expression in neonatal macrophages after stimulated with IL-6 were higher than that in adult. Significantly enhanced phosphorylation of STAT3 was seen in neonatal macrophages. Both mRNA and protein expression of SOCS3 in neonatal macrophages were lower than that in adult. After pretreated with MG132, the expression of SOCS3 protein was increased which lead to attenuate the STAT3 phosphorylation and APP gene expression. Neonatal exhibit an enhanced expression of downstream target genes and IL-6/STAT3 signal pathway which is related with the diminished SOCS3. This provides a new sight into inflammatory responses in neonatal.

SOCS3 down‐regulates ROS signaling and inhibits M1 and M2 human macrophage polarization

Initially found as feed‐back regulators of Jak/STAT pathways during cytokine signal transduction, the suppressors of cytokine signaling (SOCS) proteins have been recognized as modulators of inflammation through the regulation of macrophage activity. Macrophages are critical role players in immune‐inflammatory reactions to combat pathogen and to restore tissue homeostasis through the balanced action of distinct phenotypes: pro‐inflammatory M1 vs antiinflammatory M2. While anti‐inflammatory effect of SOCS1 through the inhibition TLR and NF‐kB signaling is well established, the role of SOCS3 in macrophage function has been controversial, being pro‐inflammatory or anti‐inflammatory. In the present work, we have studied regulatory functions of SOCS3 in inflammation employing M1 vs M2 differentiation systems and investigated the regulatory mechanisms involved. Human promonocytic THP1 cells were differentiated by PMA treatment and subject to polarization to M1 vs M2 phenotypes with LPS vs Dex stimulation, respectively for 24 to 48 h. Under such M1 or M2 differentiation condition, intracellular ROS generation and MAPK activation, albeit with different kinetics, were induced which preceded the pro‐inflammatory or anti‐inflammatory markers, respectively. Over‐expression of SOCS3 attenuated the LPS‐ or Dex‐induced ROS generation and suppressed both M1 and M2 differentiation as measured by the expression of proinflammatory (IL‐1beta, TNF‐alpha, and IL‐6) and anti‐inflammatory (TGF‐beta and IL‐10) cytokines. On the contrary, shRNA‐mediated SOCS3 knock‐down has shown the opposite effects. As a mechanism of ROS down‐regulation by SOCS3, we have observed the upregulation of anti‐oxidant factors such as Nrf‐2, Trx, SOD, and Prx in SOCS3 over‐expressing cells. Among MAPK members regulated by ROS signal, SOCS3 inhibited p38 activity critical for IL‐10 production during M2 differentiation with a prominent upregulation of MKP1. As SOCS3 suppressed STAT activation and GILZ expression important for M1 and M2 differentiation, the role of ROS signal in the regulation of these downstream transcription factors is also under investigation.Support or Funding Information&lt; Supported by NRF grants 2015‐003291 and 2016‐911262 &gt;This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Lack of SOCS3 increases LPS-induced murine acute lung injury through modulation of Ly6C(+) macrophages

BackgroundSOCS3 (suppressor of cytokine signaling 3) is a negative regulator of JAK/STAT3 signaling pathway and participates in the regulation of lung inflammation in a mouse model with acute lung injury (ALI). However, it is not well understood how SOCS3 regulates lung inflammation in the ALI mouse model.MethodIn the present study, we investigated the effects of SOCS3 on modulation of Ly6C(+) monocyte phenotypes in a mouse model with lipopolysaccharide (LPS)-induced ALI. Conditional SOCS3(Lyz2cre) mice with myeloid cell-restricted depletion of SOCS3 gene were created by breeding transgenic Lyz2Cre mice with SOCS3(fl/fl) mice. Wilde-type (WT) and SOCS3(Lyz2cre) mice were intratracheal instilled with 5 mg/kg LPS for 2 days. Lung, bronchoalveolar lavage (BAL) and blood were collected for analysis by flow cytometry, ELISA, qRT-PCR and Western blot analysis.ResultsThe studies in the ALI mouse model revealed that myeloid cell-restricted SOCS3 deficiency exacerbated the severity of ALI as compared to the WT mice. The increased severity of ALI in SOCS3-deficient mice was associated with higher populations of neutrophils, T lymphocytes and Ly6C(+) monocytes in the inflamed lung tissues. In addition, CCR2 and CXCL15 were elevated, and accompanied by greater expression and activation of STAT3 in the lung of SOCS3-deficient mice. SOCS3-deficient bone marrow-derived macrophages (BMDMs) expressed a higher amount of TNF-alpha, and adoptive transfer of the SOCS3-deficient Ly6C(+) BMDMs into WT mice enhanced the severity of ALI than adoptive transfer of WT control BMDMs. However, depletion of Ly6C(+) circulating monocytes by anti-Ly6C(+) neutralizing antibody moderately attenuated neutrophil infiltration and resulted in lower prevalence of Ly6C(+) cells in the lung of treated mice.ConclusionMyeloid cell-restricted lack of SOCS3 induced more severe ALI through modulation of Ly6C(+) subtype macrophages. The results provide insight into a new role of SOCS3 in modulation of Ly6C(+) monocyte phenotypes and provide a novel therapeutic strategy for ALI by molecular intervention of macrophages subtypes.

212 Suppressor of cytokine signalling 3 (socs3) interaction with cavin-1 links socs3 function and cavin-1 stability

Caveolae are lipid raft microdomains essential for the compartmentalisation and regulation of several signalling pathways e.g. JAK/STAT signalling. Disruption of caveolae is a significant factor in multiple disorders including muscular...

Muscle-specific deletion of SOCS3 increases the early inflammatory response but does not affect regeneration after myotoxic injury.

BackgroundMuscles of old animals are injured more easily and regenerate poorly, attributed in part to increased levels of circulating pro-inflammatory cytokines. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade is a key mediator of inflammatory cytokine action, and signaling via this pathway is increased in muscles with aging. As a negative regulator of JAK/STAT signaling, a key mediator of myogenic proliferation and differentiation, altered expression of suppressor of cytokine signaling (SOCS3) is likely to have important consequences for muscle regeneration. To model this scenario, we investigated the effect of SOCS3 deletion within mature muscle fibers on injury and repair. We tested the hypothesis that reduced SOCS3 function would alter the inflammatory response and impair muscle regeneration after myotoxic injury.MethodsMice with a specific deletion of SOCS3 within mature skeletal muscle fibers were used to assess the effect of SOCS3 deletion on muscle injury and repair. Twelve-week-old or 24-month-old SOCS3 muscle-specific knockout (SOCS3 MKO) mice and littermate controls were either left uninjured or injured with a single injection of notexin (10 μg/ml) into the right tibialis anterior (TA) muscle. At 1, 2, 3, 5, 7, or 14 days post-injury, the right TA muscle was excised and subjected to histological, western immunoblotting, and gene expression analyses. Force production and fatigue were assessed in uninjured muscles and at 7 days post-notexin injury.ResultsIn uninjured muscles, SOCS3 deletion decreased force production during fatigue but had no effect on the gross or histological appearance of the TA muscles. After notexin injury, deletion of SOCS3 increased STAT3 phosphorylation at day 1 and increased the mRNA expression of the inflammatory cytokine TNF-α, and the inflammatory cell markers F4/80 and CD68 at day 2. Gene expression analysis of the regeneration markers Pax7, MyoD, and Myogenin indicated SOCS3 deletion had no effect on the progression of muscle repair after notexin injury. Inflammation and regeneration were also unchanged in the muscles of 24-month-old SOCS3 MKO mice compared with control.ConclusionsLoss of SOCS3 expression in mature muscle fibers increased the inflammatory response to myotoxic injury but did not impair muscle regeneration in either adult or old mice. Therefore, reduced SOCS3 expression in muscle fibers is unlikely to underlie impaired muscle regeneration. Further investigation into the role of SOCS3 in other cell types involved in muscle repair is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0108-4) contains supplementary material, which is available to authorized users.

MiR-124-3p/B4GALT1 axis plays an important role in SOCS3-regulated growth and chemo-sensitivity of CML.

BackgroundAbnormal expression of SOCS3 has been implicated in myeloproliferative neoplasms, but the role of SOCS3 in the pathogenesis of leukemia remains largely unknown. Here, we examined the function of SOCS3 in the growth and chemo-sensitivity of chronic myeloid leukemia (CML) and explored the involved mechanisms.MethodsExpression levels of SOCS3 in several leukemia cell lines and bone marrow mononuclear cells (BMNCs) from CML patients were determined using quantitative real-time PCR (qPCR) and Western blotting (WB). The roles of SOCS3 in the proliferation, apoptosis, and drug resistance of CML cells were examined by clonogenic progenitor cell assay, flow cytometry, and CCK-8 assay. A detailed analysis of the underlying mechanism of SOCS3 in K562 cells was performed using the Human HT-12 v4 Expression BeadChip, which has more than 48000 gene probes including 600 microRNAs (miRNA) probes. The correlation between the mRNA expression of SOCS3 and miR-124-3p in BMNCs from 30 CML patients was tested by qPCR and analyzed by Pearson correlation and linear regression analysis. The potential target of miR-124-3p in CML cells was explored using the luciferase reporter assay, qPCR, and WB. The effect of SOCS3 on the miR-124-3p/B4GALT1 axis was investigated by qPCR, WB, CCK-8 assay, and tumorigenicity assays in nude mice.ResultsSOCS3 was down-regulated in CML cell lines and most of BMNCs from CML patients, and the expression level of SOCS3 was associated with the inhibition of cell proliferation and drug resistance of CML cells. Over-expression of SOCS3 in K562 cells inhibited the expression of leukemia-specific genes and promoted the expression of some miRNAs, among which miR-124-3p was the highest. SOCS3 over-expression enhanced the expression of miR-124-3p and vice versa. The mRNA expression of miR-124-3p and SOCS3 in BMNCs from 30 CML patients was positively correlated. Consistently, the tumor suppressing effects of SOCS3 were partially neutralized by the miR-124-3p inhibitor. B4GALT1 was downstream of miR-124-3p and regulated by SOCS3/miR-124-3p in vitro. Furthermore, SOCS3 over-expression could inhibit the growth and B4GALT expression of K562 cells in vivo.ConclusionsSOCS3/miR-124-3p/B4GALT1 axis plays an important role in the pathogenesis of CML.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0300-3) contains supplementary material, which is available to authorized users.

Suppressor of Cytokine Signaling 3 Is a Negative Regulator for Neointimal Hyperplasia of Vein Graft Stenosis

Coronary artery bypass graft (CABG) surgery is one of the most effective treatments for coronary artery disease. However, neointimal hyperplasia and ultimate luminal occlusion that is caused by vascular smooth muscle cell (VSMC) migration, proliferation and inflammatory response impede the long-term prognosis. The SOCS3 protein is involved in modulating various autoimmune and inflammatory diseases. However, the role of SOCS3 in vein graft disease is still unclear. We found that the mRNA and protein expression levels of IL-1β, IL-6, MCP-1, ICAM-1, TNF-α, STAT3, P-STAT3 and SOCS3 were significantly higher in the graft samples compared to normal veins. After transfecting the recombinant adenovirus carrying the rat SOCS3 gene into cultured rat VSMCs or grafting veins in rat, SOCS3 overexpression was found to significantly inhibit VSMC migration and proliferation in vitro and neointimal hyperplasia in vivo, respectively. Furthermore, SOCS3 overexpression inhibited VSMC migration and growth in vitro and alleviated VSMC inflammation in vitro by inhibiting STAT3 activation and phosphorylation. In conclusion, SOCS3 is a crucial physiological negative regulator for vein graft failure and provides a novel target for vein graft stenosis therapy after CABG.

Abstract A80: Role of myeloid SOCS3 in prostate cancer progression.

Abstract Suppressor Of Cytokine Signaling (SOCS) proteins, negative regulators of the JAK/STAT pathway, have been implicated in having a key protective role in tumor initiation and progression. However, the role of SOCS3 in regulating the differentiation and functions of myeloid-derived suppressor cells (MDSC) is poorly understood. Recent studies show the important role of MDSCs in promoting tumor progression as well as metastasis by regulating immune surveillance. To determine the role of myeloid SOCS3 in tumor progression, Conditional SOCS3 deletion in myeloid cells (LysMCre-SOCS3fl/fl) and SOCS3fl/fl C57BL/6 mice were used as recipients for subcutaneous transplantation of TRAMP-derived mouse prostate tumor cells. Our results indicate that tumor growth is significantly enhanced in myeloid-specific SOCS3-deficient mice, which correlates with elevated levels of Gr1+/CD11b+ cells in both spleen and tumor, and less CD8+ T-cell infiltration in tumors. Tumors from myeloid-specific SOCS3-deficient mice also express high levels of Arginase-1 and have elevated Akt signaling. In vitro, SOCS3-deficient bone-marrow-derived mononuclear cells (BDMC) exhibit heightened STAT3 activation and are subject to differentiation towards the MDSC phenotype. These findings suggest that myeloid cell SOCS3 provides protection from tumor progression by regulating MDSC differentiation. Citation Format: Hao Yu, Yudong Liu, Etty N. Benveniste, Hongwei Qin. Role of myeloid SOCS3 in prostate cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A80.

SOCS3 promotes interleukin-17 expression of human T cells

AbstractSOCS3 is a feedback regulator of cytokine signaling that affects T-cell polarization. Human tuberculosis is accompanied by increased SOCS3 expression in T cells, and this may influence susceptibility against Mycobacterium tuberculosis. Because the role of SOCS3 in human T-cell function is not well defined, we characterized cytokine expression and proliferation of human T cells with differential SOCS3 expression in the present study. We established a flow cytometry–based method for SOCS3 protein quantification and detected higher SOCS3 levels induced by M tuberculosis specific T-cell activation and a transient decrease of SOCS3 expression in the presence of mycobacteria-infected macrophages. Notably increased SOCS3 expression was detected in IL-17–expressing T-cell clones and in CD161+ T helper type 17 cells ex vivo. Ectopic SOCS3 expression in primary CD4+ T cells by lentiviral transduction induced increased IL-17 production but diminished proliferation and viability. Recombinant IL-7 inhibited SOCS3 expression and reduced IL-17–expressing T-cell proportions. We concluded that higher SOCS3 expression in human T cells favors T helper type 17 cells. Therefore, increased SOCS3 expression in human tuberculosis may reflect polarization toward IL-17–expressing T cells as well as T-cell exhaustion marked by reduced proliferation.

O016 Inhibition of the JAK/STAT pathway protects against neuroinflammation

Introduction Suppressor Of Cytokine Signaling (SOCS) proteins are feedback inhibitors of the JAK/STAT pathway. SOCS3 has a crucial role in inhibiting STAT activation, cytokine signaling and inflammatory gene expression in macrophages/microglia. Methods To determine the role of SOCS3 in myeloid cells in neuroinflammation, mice with conditional SOCS3 deletion in myeloid cells (LysMCre-SOCS3fl/fl) were tested for experimental autoimmune encephalomyelitis (EAE). Results The myeloid specific SOCS3-deficient mice are vulnerable to MOG-induced EAE, with a severe, non-resolving atypical form of disease. In vivo, enhanced infiltration of inflammatory cells and demyelination is prominent in the cerebellum of myeloid specific SOCS3-deficient mice, as is enhanced STAT3/4 signaling and expression of inflammatory cytokines/chemokines, and an immune response dominated by Th1 and Th17 cells. In vitro, SOCS3-deficient macrophages exhibit heightened STAT3 activation, and are polarized toward the classical M1 phenotype. SOCS3-deficient M1 macrophages provide the microenvironment to polarize Th1 and Th17 cells and induce neuronal death. Furthermore, adoptive transfer of anti-inflammatory M2 macrophages into myeloid SOCS3-deficient mice leads to delayed onset and reduced severity of atypical EAE by decreasing STAT3 activation, Th1/Th17 cells and proinflammatory mediators in the cerebellum. These findings indicate that myeloid cell SOCS3 provides protection from EAE through deactivation of neuroinflammatory responses. LysMCre-SOCS3fl/fl mice are also protected from atypical EAE by the administration of a JAK/STAT3 inhibitor, AZD1480. Severity of disease is attenuated, which is associated with a reduction in STAT1/3 activation, less Th1/Th17 cell infiltration in the cerebellum, reductions in inflitrating neutrophils and macrophages, and decreased M1 proinflammatory gene expression. Mice with classical EAE are also protected against disease severity by treatment with AZD1480. Conclusion Collectively, these findings indicate the JAK/STAT3 signaling pathway may serve as a therapeutic target for neuroinflammatory diseases.

Constitutive expression of suppressor of cytokine signalling-3 in skeletal muscle leads to reduced mobility and overweight in mice

Due to their ability to regulate various signalling pathways (cytokines, hormones, growth factors), the suppressor of cytokine signalling (SOCS) proteins are thought to be promising therapeutic targets for metabolic and inflammatory disorders. Hence, their role in vivo has to be precisely determined. We generated transgenic mice constitutively producing SOCS-3 in skeletal muscle to define whether the sole abundance of SOCS-3 is sufficient to induce metabolic disorders and whether SOCS-3 is implicated in physiological roles distinct from metabolism. We demonstrate here that chronic expression of SOCS-3 in skeletal muscle leads to overweight in mice and worsening of high-fat diet-induced systemic insulin resistance. Counter-intuitively, insulin sensitivity in muscle of transgenic mice appears to be unaltered. However, following constitutive SOCS-3 production, several genes had deregulated expression, among them other members of the SOCS family. This could maintain the insulin signal into skeletal muscle. Interestingly, we found that SOCS-3 interacts with calcineurin, which has been implicated in muscle contractility. In Socs-3 transgenic muscle, this leads to delocalisation of calcineurin to the fibre periphery. Relevant to this finding, Socs-3 transgenic animals had dilatation of the sarcoplasmic reticulum associated with swollen mitochondria and decreased voluntary activity. Our results show that constitutive SOCS-3 production in skeletal muscle is not in itself sufficient to induce the establishment of metabolic disorders such as diabetes. In contrast, we reveal a novel role of SOCS-3, which appears to be important for muscle integrity and locomotor activity.

The expression of SOCS-3 in peripheral blood mononuclear cells in the septic patients

Objective To explore of the role of SOCS-3 in the pathogenesss of sepsis. Methods The expression of SOCS-3 mRNA in peripheral blood mononuelear cells in 36 patients with sepsis and 30 healthy vol-unteers was measured by RT-PCR. The correlation analysis between The expression of SOCS-3 mRNA in periph- end blood mononuelear cells and the septic patient's scores of APACHE 11 was made. Results The expression of SOCS-3 mRNA in peripheral blood mononuclear cells in the sepsis group and the control group were found. The level of SOCS-3 mRNA in the sepsis group were significantly higher than those in the control group ( P <0. 001 ). The expression of SOCS-3 mRNA have a significant negative correlation with the septic patient's scores of APACHE Ⅱ ,the correlation coeffieient(r)was-0.746(P <0.01). Conclusions SOCS-3 have a role in the pathogenesis of sepsis. The expression of SOCS-3 mRNA may have protection in septic patients. Key words: SOCS-3; Sepsis; Peripheral blood mononuclear cells

SOCS3 in Liver Regeneration and Hepatocarcinoma

Cytokine responses are stringently controlled by a family of proteinsSTAT3 termed the suppressors of cytokine signaling (SOCS), and deregulation of SOCS function is associated with many diseases, including several cancers, disorders in hematopoiesis, and autoimmune diseases. Our current understanding of the divergent roles of SOCS3 has recently improved and indicates that SOCS3 is critical in modulating cytokine-mediated and neoplastic-proliferative responses in the liver. The generation of hepatocyte-specific Socs3 knockout mice suggests that loss of SOCS3 expression encourages hepatocyte proliferation, survival, and hepatocellular carcinoma formation. By elucidating the regulation of pathways leading to liver regeneration we may gain useful insights to control liver disease and tumor growth.

Role of SOCS-3 in Obesity and Diabetes Mellitus

SOCS-3是细胞因子信号传导抑制因子(SOCS)家族成员之一,作为JAK-STAT通路的负反馈抑制因子,一方面在瘦素抵抗所致的肥胖中起重要作用,并且在其他细胞因子刺激下调节脂代谢;另一方面SOCS-3作用于胰岛素与受体结合到最后靶分子过程中的多个环节,抑制胰岛素信号传导,导致胰岛素抵抗,从而引起2型糖尿病.但SOCS-3与1型糖尿病的关系尚不明确。