scholarly journals Silenced suppressor of cytokine signaling 1 (SOCS1) enhances the maturation and antifungal immunity of dendritic cells in response to Candida albicans in vitro

2014 ◽  
Vol 61 (3) ◽  
pp. 206-218 ◽  
Author(s):  
Dongmei Shi ◽  
Dongmei Li ◽  
Qingxin Yin ◽  
Ying Qiu ◽  
Hongxia Yan ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Candida Albicans ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Antifungal Immunity

scholarly journals Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jatin Sharma ◽  
Teresa D. Collins ◽  
Tracoyia Roach ◽  
Shiwangi Mishra ◽  
Brandon K. Lam ◽  
...  
Keyword(s):  
Intraperitoneal Administration ◽  
Lymphocyte Activation ◽  
Signal Propagation ◽  
Skin Lesions ◽  
Effector Memory ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Autoantibody Production ◽  
Ifn Γ

AbstractAutoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Faslpr/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of GL7+ germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.

Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christina Grothusen ◽  
Harald Schuett ◽  
Stefan Lumpe ◽  
Andre Bleich ◽  
Silke Glage ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

scholarly journals Sox2 controls neural stem cell self-renewal through a Fos-centered gene regulatory network

2020 ◽  
Author(s):  
Miriam Pagin ◽  
Simone Giubbolini ◽  
Cristiana Barone ◽  
Gaia Sambruni ◽  
Yanfen Zhu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cytokine Signaling ◽  
Normal Brain ◽  
Suppressor Of Cytokine Signaling ◽  
Self Renewal ◽  
Upstream Regulator ◽  
Socs3 Expression ◽  
Pharmacological Manipulations

AbstractThe Sox2 transcription factor is necessary for the long-term self-renewal of neural stem cells (NSC). Its mechanism of action is still poorly defined. To identify molecules regulated by Sox2, and acting in mouse NSC maintenance, we transduced, individually or in combination, into Sox2-deleted NSC, genes whose expression is strongly downregulated following Sox2 loss (Fos, Jun, Egr2). Fos alone rescued long-term proliferation, as shown by in vitro cell growth and clonal analysis. Further, Fos requirement for efficient long-term proliferation was demonstrated by the strong reduction of NSC clones capable of long-term expansion following CRISPR/Cas9-mediated Fos inactivation. Previous work showed that the Suppressor of cytokine signaling 3 (Socs3) gene is strongly downregulated following Sox2 deletion, and its reexpression by lentiviral transduction rescues long-term NSC proliferation. Fos appears to be an upstream regulator of Socs3, possibly together with Jun and Egr2; indeed, Sox2 reexpression in Sox2-deleted NSC progressively activates both Fos and Socs3 expression; in turn, Fos transduction activates Socs3 expression. Based on available SOX2 ChIPseq and ChIA-PET data, as well as results from the literature, we propose a model whereby Sox2 is a direct activator of both Socs3 and Fos, as well as possibly Jun and Egr2; in turn, Fos, Jun and Egr2 may activate Socs3. These results provide the basis for developing a model of a network of interactions, regulating critical effectors of NSC proliferation and long-term maintenance.Significance statementProliferation and maintenance of NSC are essential during normal brain development, and, postnatally, for the maintenance of hippocampal function and memory until advanced age. Little is known about the molecular mechanisms that maintain the critical aspects of NSC biology (quiescence and proliferation) in postnatal age. Our work provides a methodology, transduction of genes deregulated following Sox2 deletion, that allows to test many candidate genes for their ability to sustain NSC proliferation. In principle, this may have interesting implications for identifying targets for pharmacological manipulations.

scholarly journals Thymus-Derived Regulatory T Cell Development Is Regulated by C-Type Lectin-Mediated BIC/MicroRNA 155 Expression

2017 ◽  
Vol 37 (9) ◽  
Author(s):  
Raquel Sánchez-Díaz ◽  
Rafael Blanco-Dominguez ◽  
Sandra Lasarte ◽  
Katerina Tsilingiri ◽  
Enrique Martín-Gayo ◽  
...  
Keyword(s):  
Treg Cell ◽  
Feedback Loop ◽  
Cell Development ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Hairpin Rna ◽  
Lectin Receptor ◽  
Reporter Mice ◽  
Itreg Cell

ABSTRACT Thymus-derived regulatory T (tTreg) cells are key to preventing autoimmune diseases, but the mechanisms involved in their development remain unsolved. Here, we show that the C-type lectin receptor CD69 controls tTreg cell development and peripheral Treg cell homeostasis through the regulation of BIC/microRNA 155 (miR-155) and its target, suppressor of cytokine signaling 1 (SOCS-1). Using Foxp3-mRFP/cd69 +/− or Foxp3-mRFP/cd69 −/− reporter mice and short hairpin RNA (shRNA)-mediated silencing and miR-155 transfection approaches, we found that CD69 deficiency impaired the signal transducer and activator of transcription 5 (STAT5) pathway in Foxp3+ cells. This results in BIC/miR-155 inhibition, increased SOCS-1 expression, and severely impaired tTreg cell development in embryos, adults, and Rag2−/− γc−/− hematopoietic chimeras reconstituted with cd69 −/− stem cells. Accordingly, mirn155 −/− mice have an impaired development of CD69+ tTreg cells and overexpression of the miR-155-induced CD69 pathway, suggesting that both molecules might be concomitantly activated in a positive-feedback loop. Moreover, in vitro-inducible CD25+ Treg (iTreg) cell development is inhibited in Il2rγ−/−/cd69 −/− mice. Our data highlight the contribution of CD69 as a nonredundant key regulator of BIC/miR-155-dependent Treg cell development and homeostasis.

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