SOCS3 negatively regulates IL-6 signaling in vivo

Croker, Ben A.; Krebs, Danielle L.; Zhang, Jianguo; Wormald, Sam; Willson, Tracy A.; Stanley, Edouard G.; Robb, Lorraine; Greenhalgh, Christopher J.; Förster, Irmgard; Clausen, Björn E.; Nicola, Nicos A.; Metcalf, Donald; Hilton, Douglas J.; Roberts, Andrew W.; Alexander, Warren S.

doi:10.1038/ni931

Cited by 735 publications

(682 citation statements)

References 38 publications

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“…1b). Thereafter, STAT3 phosphorylation induced by IL-10 decays slowly, whereas STAT3 phosphorylation induced by IL-6 has a faster decay, an effect dependent on SOCS3-mediated inhibition of IL-6 signaling (20,31,32). Similar findings were obtained using BMDMs stimulated with IL-10 or IL-6 in the presence of LPS as a proinflammatory costimulus (data not shown).…”

Section: Elimination Of Socs3 Binding Allows the Il-6r To Generate Thsupporting

confidence: 74%

“…By comparison, another stereotypical STAT signaling pathway is the STAT1-mediated IFN response. Like the AIR, the STAT1-mediated IFN response can be generated from receptors other than the IFN receptors by manipulating levels of key signaling components (20,31,40). The findings we reported have implications for understanding the AIR in cells other than IL-10-responsive macrophages.…”

Section: Discussionmentioning

confidence: 78%

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General Nature of the STAT3-Activated Anti-Inflammatory Response

Kasmi

Holst²,

Coffre

et al. 2006

The Journal of Immunology

199

179

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Although many cytokine receptors generate their signals via the STAT3 pathway, the IL-10R appears unique in promoting a potent anti-inflammatory response (AIR) via STAT3 to antagonize proinflammatory signals that activate the innate immune response. We found that heterologous cytokine receptor systems that activate STAT3 but are naturally refractory (the IL-22R), or engineered to be refractory (the IL-6, leptin, and erythropoietin receptors), to suppressor of cytokine signaling-3-mediated inhibition activate an AIR indistinguishable from IL-10. We conclude that the AIR is a generic cytokine signaling pathway dependent on STAT3 but not unique to the IL-10R.

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Section: Elimination Of Socs3 Binding Allows the Il-6r To Generate Thsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 78%

General Nature of the STAT3-Activated Anti-Inflammatory Response

Kasmi

Holst²,

Coffre

et al. 2006

The Journal of Immunology

199

179

View full text Add to dashboard Cite

show abstract

“…Furthermore, periarticular adenoviral overexpression of SOCS-3 is effective in attenuating collagen-induced arthritis in mice (31). SOCS proteins, however, might redirect signaling pathways in a concentration-dependent manner (32)(33)(34). In the absence of SOCS-3, prolonged STAT-3 and STAT-1 activation has been observed in vitro and in vivo after stimulation with IL-6.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of SOCS-3, prolonged STAT-3 and STAT-1 activation has been observed in vitro and in vivo after stimulation with IL-6. The prolonged STAT-1 activation most likely contributed to the IFN␥-like gene expression in response to IL-6 (33,34).…”

Section: Discussionmentioning

confidence: 99%

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

Hooge¹,

Loo²,

Koenders³

et al. 2004

Arthritis & Rheumatism

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Objective. STAT proteins play an important role in cytokine signaling. Some investigators have reported preferential activation of STAT-1, and others have reported preferential activation of STAT-3, in response to endogenous interleukin-6 (IL-6), in patients with rheumatoid arthritis. The present study was undertaken to investigate synovial STAT-1 and STAT-3 activation in an experimental animal model of arthritis.Methods. Zymosan was injected intraarticularly into naive wild-type (WT), IL-6 ؊/؊ , and STAT-1 ؊/؊ mice to induce arthritis. Western blots of synovial lysates were probed with phosphospecific antibodies to detect STAT-1/STAT-3 activation. Inflammation was assessed histologically. Synovial gene expression of the STATinduced feedback inhibitors suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 in WT and STAT-1 ؊/؊ mice was investigated by reverse transcriptasepolymerase chain reaction.Results. STAT-3 was activated in inflamed synovium of WT mice throughout the course of disease, whereas activated STAT-1 was observed only during the chronic phase. In IL-6 ؊/؊ mice, STAT activation was limited to STAT-3 on day 1. Although macrophage influx was not inhibited, disease went into remission after day 7 in IL-6 ؊/؊ mice. STAT-1 deficiency resulted in exacerbation of chronic joint inflammation and granuloma formation. In STAT-1 ؊/؊ mice, STAT-3 activation in the inflamed joints was unaltered as compared with WT mice. However, synovial SOCS-1, but not SOCS-3, gene expression was markedly reduced in STAT-1 ؊/؊ mice.Conclusion. The results in the IL-6 ؊/؊ mice suggest that STAT-3 is involved in the chronicity of ZIA. Exacerbation of arthritis in STAT-1 ؊/؊ mice suggests an opposing effect of STAT-1, i.e., suppression of joint inflammation. The expression of SOCS-1 could be the underlying mechanism by which STAT-1 controls joint inflammation.

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“…In contrast, SOCS3, a negative feedback regulator of the JAK−STAT3 pathway, markedly increased in these Senp1-silenced macrophages upon treatment ( Figure 2B and C). Since SOCS3 negatively regulates JAK activity in macrophages in response to IL-6 stimulation (Croker et al, 2003), we speculated that increased expression of SOCS3 might be responsible for the downregulation of JAK2 activity in SENP1-deficient macrophages. To verify this, we silenced Socs3 in si-SENP1-RAW264.7 cells (Supplementary Figure S6) and examined the gene induction by IFN-γ in these cells.…”

Section: Stat3−socs3 Mediates An Alternative Feedback Inhibition Of Imentioning

confidence: 99%

SENP1 regulates IFN-γ−STAT1 signaling through STAT3−SOCS3 negative feedback loop

Zuo

Cai

et al. 2016

Journal of Molecular Cell Biology

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Interferon-γ (IFN-γ) triggers macrophage for inflammation response by activating the intracellular JAK−STAT1 signaling. Suppressor of cytokine signaling 1 (SOCS1) and protein tyrosine phosphatases can negatively modulate IFN-γ signaling. Here, we identify a novel negative feedback loop mediated by STAT3−SOCS3, which is tightly controlled by SENP1 via de-SUMOylation of protein tyrosine phosphatase 1B (PTP1B), in IFN-γ signaling. SENP1-deficient macrophages show defects in IFN-γ signaling and M1 macrophage activation. PTP1B in SENP1-deficient macrophages is highly SUMOylated, which reduces PTP1B-induced de-phosphorylation of STAT3. Activated STAT3 then suppresses STAT1 activation via SOCS3 induction in SENP1-deficient macrophages. Accordingly, SENP1-deficient macrophages show reduced ability to resist Listeria monocytogenes infection. These results reveal a crucial role of SENP1-controlled STAT1 and STAT3 balance in macrophage polarization.

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SOCS3 negatively regulates IL-6 signaling in vivo

Cited by 735 publications

References 38 publications

General Nature of the STAT3-Activated Anti-Inflammatory Response

General Nature of the STAT3-Activated Anti-Inflammatory Response

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

SENP1 regulates IFN-γ−STAT1 signaling through STAT3−SOCS3 negative feedback loop

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