TLR-induced negative regulatory circuits: role of suppressor of cytokine signaling (SOCS) proteins in innate immunity

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.

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Inducible microRNA-155 Feedback Promotes Type I IFN Signaling in Antiviral Innate Immunity by Targeting Suppressor of Cytokine Signaling 1

The Journal of Immunology ◽

10.4049/jimmunol.1000491 ◽

2010 ◽

Vol 185 (10) ◽

pp. 6226-6233 ◽

Cited By ~ 277

Author(s):

Pin Wang ◽

Jin Hou ◽

Li Lin ◽

Chunmei Wang ◽

Xingguang Liu ◽

...

Keyword(s):

Innate Immunity ◽

Cytokine Signaling ◽

Type I ◽

Type I Ifn ◽

Suppressor Of Cytokine Signaling ◽

Antiviral Innate Immunity

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Effects of Ecklonia cava ethanolic extracts on airway hyperresponsiveness and inflammation in a murine asthma model: Role of suppressor of cytokine signaling

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2007.07.009 ◽

2008 ◽

Vol 62 (5) ◽

pp. 289-296 ◽

Cited By ~ 59

Author(s):

Se-Kwon Kim ◽

Da-Young Lee ◽

Won-Kyo Jung ◽

Ji-Hye Kim ◽

Inhak Choi ◽

...

Keyword(s):

Airway Hyperresponsiveness ◽

Ecklonia Cava ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Asthma Model ◽

Ethanolic Extracts ◽

Murine Asthma Model

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Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2015-0036 ◽

2016 ◽

Vol 26 (1) ◽

Cited By ~ 5

Author(s):

Amira Alkharusi ◽

Mercedes Mirecki-Garrido ◽

Zuheng Ma ◽

Fahad Zadjali ◽

Amilcar Flores-Morales ◽

...

Keyword(s):

Type I Diabetes ◽

Janus Kinase ◽

Cytokine Signaling ◽

Type I ◽

Suppressor Of Cytokine Signaling ◽

Β Cell ◽

Diabetes In Mice ◽

Socs Proteins ◽

Stat Pathway

AbstractDiabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity.The elevated sensitivity of SOCS2We show that 6-month-old SOCS2Knockdown of SOCS2 makes mice less sensitive to MLDSTZ. These results are consistent with the proposal that elimination of SOCS2 in pancreatic islets creates a state of β-cell hypersensitivity to GH/PRL that mimics events in pregnancy, and which is protective against MLDSTZ-induced type I diabetes in mice. SOCS2-dependent control of β-cell survival may be of relevance to islet regeneration and survival in transplantation.

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miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1

Blood ◽

10.1182/blood-2010-12-322503 ◽

2011 ◽

Vol 117 (16) ◽

pp. 4293-4303 ◽

Cited By ~ 182

Author(s):

Changming Lu ◽

Xin Huang ◽

Xiaoxiao Zhang ◽

Kristin Roensch ◽

Qing Cao ◽

...

Keyword(s):

Cytokine Signaling ◽

Wild Type ◽

Suppressor Of Cytokine Signaling ◽

Hematopoietic Progenitor ◽

Monocyte Differentiation ◽

P27kip1 Protein ◽

And Function ◽

Antigen Presenting ◽

Dc Maturation

Abstract Dendritic cells (DCs) are potent antigen-presenting cells derived from hematopoietic progenitor cells and circulating monocytes. To investigate the role of microRNAs (miRNAs) during DC differentiation, maturation, and function, we profiled miRNA expression in human monocytes, immature DCs (imDCs), and mature DCs (mDCs). Stage-specific, differential expression of 27 miRNAs was found during monocyte differentiation into imDCs and mDCs. Among them, decreased miR-221 and increased miR-155 expression correlated with p27kip1 accumulation in DCs. Silencing of miR-221 or overexpressing of miR-155 in DCs resulted in p27kip1 protein increase and DC apoptosis. Moreover, mDCs from miR-155−/− mice were less apoptotic than those from wild-type mice. Silencing of miR-155 expression had little effect on DC maturation but reduced IL-12p70 production, whereas miR-155 overexpression in mDCs enhanced IL-12p70 production. Kip1 ubiquitination-promoting complex 1, suppressor of cytokine signaling 1, and CD115 (M-CSFR) were functional targets of miR-155. Furthermore, we provide evidence that miR-155 indirectly regulated p27kip1 protein level by targeting Kip1 ubiquitination-promoting complex 1. Thus, our study uncovered miRNA signatures during monocyte differentiation into DCs and the new regulatory role of miR-221 and miR-155 in DC apoptosis and IL-12p70 production.

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