Inhibition of SOCS1−/− Lethal Autoinflammatory Disease Correlated to Enhanced Peripheral Foxp3+ Regulatory T Cell Homeostasis

Collins, Erin; Jager, Lindsey D.; Dabelic, Rea; Benitez, Patrick; Holdstein, Kaitlin; Lau, Kenneth; Haider, Mohammed I.; Johnson, Howard M.; Larkin, Joseph

doi:10.4049/jimmunol.1003819

Cited by 27 publications

(44 citation statements)

References 54 publications

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“…SOCS1, a well-established member of the SOCS family, has been shown to be involved in the differentiation and activation of T-helper cells [31,32,33,34,35]. We found that SOCS1 mRNA expression was decreased in PBMCs from ITP patients, which implied that SOCS1 was also involved in the pathogenesis of ITP.…”

Section: Discussionsupporting

confidence: 49%

Increased miR-155 Expression in Peripheral Blood Mononuclear Cells of Primary Immune Thrombocytopenia Patients Was Correlated with Serum Cytokine Profiles

Bian

Zhang³

et al. 2014

Acta Haematol

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We investigated the possiblepathogenic role of a microRNA (miR-155) in primary immune thrombocytopenia (ITP). We used quantitative real-time PCR to determine the relative expression of miR-155 and SOCS1 (suppressor of cytokine signaling) mRNA in peripheral blood mononuclear cells (PBMCs) from 28 ITP patients and 28 healthy controls. Cytokine plasma levels were determined by ELISA. Possible associations between miR-155 levels and serum cytokine concentrations were assessed using Spearman or Pearson correlation analysis. Seven naive ITP patients were followed and the effects of medical treatment on miR-155 levels were assessed. Compared to healthy controls, ITP patients had increased miR-155 and decreased SOCS1 mRNA levels. ITP patients also had increased plasma IL-17A and decreased IL-4, IL-10 and TGF-β₁ levels. miR-155 levels were negatively correlated with platelet counts, SOCS1 mRNA levels, and the plasma levels of IL-4, IL-10 and TGF-β₁, but positively correlated with plasma IL-17A levels. Medical treatment for ITP decreased miR-155 levels. Thus, our results suggest that miR-155 might be involved in the pathogenesis of ITP by regulating cytokine profiles, which may be mediated by miR-155 targeting SOCS1. © 2014 S. Karger AG, Basel

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Section: Discussionsupporting

confidence: 49%

Increased miR-155 Expression in Peripheral Blood Mononuclear Cells of Primary Immune Thrombocytopenia Patients Was Correlated with Serum Cytokine Profiles

Bian

Zhang³

et al. 2014

Acta Haematol

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“…Significantly, lipo-SOCS1-KIR administration, in combination with CD4 T cell adoptive transfer, was sufficient to extend the survival of SOCS1 −/− mice (78). The survival of the SOCS1 −/− mice receiving the combined treatment was similar to previous studies utilizing mice where SOCS1 contained a KIR region, but lacked a SOCS box (65).…”

Section: Socs Mimetics As Therapeutics Against Auto-immunity and Inflmentioning

confidence: 99%

Regulation of Interferon Gamma Signaling by Suppressors of Cytokine Signaling and Regulatory T Cells

et al. 2013

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Regulatory T cells (Tregs) play an indispensable role in the prevention of autoimmune disease, as interferon gamma (IFNγ) mediated, lethal auto-immunity occurs (in both mice and humans) in their absence. In addition, Tregs have been implicated in preventing the onset of autoimmune and auto-inflammatory conditions associated with aberrant IFNγ signaling such as type 1 diabetes, lupus, and lipopolysaccharide (LPS) mediated endotoxemia. Notably, suppressor of cytokine signaling-1 deficient (SOCS1−/−) mice also succumb to a lethal auto-inflammatory disease, dominated by excessive IFNγ signaling and bearing similar disease course kinetics to Treg deficient mice. Moreover SOCS1 deficiency has been implicated in lupus progression, and increased susceptibility to LPS mediated endotoxemia. Although it has been established that Tregs and SOCS1 play a critical role in the regulation of IFNγ signaling, and the prevention of lethal auto-inflammatory disease, the role of Treg/SOCS1 cross-talk in the regulation of IFNγ signaling has been essentially unexplored. This is especially pertinent as recent publications have implicated a role of SOCS1 in the stability of peripheral Tregs. This review will examine the emerging research findings implicating a critical role of the intersection of the SOCS1 and Treg regulatory pathways in the control of IFN gamma signaling and immune system function.

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“…Mice deficient in SOCS1 die of 100% lethal, perinatal auto‐inflammatory disease with excessive STAT1 activation. We have previously shown that in vivo administration of a peptide that mimicked the kinase inhibitory region of SOCS1 (SOCS1‐KIR) to SOCS1 deficient mice prolonged life, limited IFN‐gamma production and enhanced Foxp3 + regulatory T cells . Although a positive correlation between SOCS1 and SOCS3 message levels was observed in both SLE patients and healthy controls, the overall levels were reduced in SLE patients.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential for Targeting the Suppressor of Cytokine Signalling‐1 Pathway for the Treatment of SLE

Sukka-Ganesh

Larkin

2016

Scand J Immunol

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Although the specific events dictating systemic lupus erythematosus (SLE) pathology remain unclear, abundant evidence indicates a critical role for dysregulated cytokine signaling in disease progression. Notably, the suppressor of cytokine signaling (SOCS) family of intracellular proteins, in particular the kinase inhibitory region (KIR) bearing SOCS1 and SOCS3, play a critical role in regulating cytokine signaling. To assess a relationship between SOCS1/SOCS3 expression and SLE, the goals of this study were to: 1) evaluate the time kinetics of SOCS1/SOCS3 message and protein expression based on SLE associated stimulations, 2) compare levels of SOCS1 and SOCS3 present in SLE patients and healthy controls by message and protein, 3) relate SOCS1/SOCS3 expression to inflammatory markers in SLE patients, and 4) correlate SOCS1/SOCS3 levels to current treatments. We found that SOCS1 and SOCS3 were most abundant in murine splenic samples at 48 hours subsequent to stimulation by anti-CD3, LPS, or interferon gamma. In addition, significant reductions in SOCS1 and SOCS3 were present within PMBC’s of SLE patients compared to controls by both mRNA and protein expression. We also found that decreased levels of SOCS1 in SLE patients were correlated to enhanced levels of inflammatory markers and up-regulated expression of MHC class II. Finally, we show that patients receiving steroid treatment possessed higher levels SOCS1 compared to SLE patient counterparts, and that steroid administration to human PBMCs up-regulated SOCS1 message in a dose and time dependent manner. Together, these results suggest that therapeutic strategies focused on SOCS1 signaling may have efficacy in the treatment of SLE.

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Inhibition of SOCS1−/− Lethal Autoinflammatory Disease Correlated to Enhanced Peripheral Foxp3+ Regulatory T Cell Homeostasis

Cited by 27 publications

References 54 publications

Increased miR-155 Expression in Peripheral Blood Mononuclear Cells of Primary Immune Thrombocytopenia Patients Was Correlated with Serum Cytokine Profiles

Increased miR-155 Expression in Peripheral Blood Mononuclear Cells of Primary Immune Thrombocytopenia Patients Was Correlated with Serum Cytokine Profiles

Regulation of Interferon Gamma Signaling by Suppressors of Cytokine Signaling and Regulatory T Cells

Therapeutic Potential for Targeting the Suppressor of Cytokine Signalling‐1 Pathway for the Treatment of SLE

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