Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity

Fenner, Jennifer Eve; Starr, Robyn; Cornish, Ann L.; Zhang, Jianguo; Metcalf, Donald; Schreiber, Robert D.; Sheehan, Kathleen C. F.; Hilton, Douglas J.; Alexander, Warren S.; Hertzog, Paul J.

doi:10.1038/ni1287

Cited by 250 publications

(205 citation statements)

References 51 publications

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“…Recent studies have demonstrated that SOCS1 associates directly with IFNAR1, a component of the type 1 IFN receptor, thereby blocking activation of STAT1. 49 The magnitude and synchrony of the in vivo downregulation of ISG transcription, especially in the presence of circulating peg-IFN-␣, was not anticipated, but clearly must be evaluated for its role in the kinetics of viral clearance of HCV during IFN-␣ therapy. The duration of the downregulation was not determined in this study but must exceed 24 hours.…”

Section: Discussionmentioning

confidence: 99%

Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

et al. 2006

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The mechanism of the interferon-alpha (IFN-␣)-induced antiviral response during hepatitis C virus (HCV) therapy is not completely understood. In this study, we examined the transcriptional response to IFN-␣ in uninfected chimpanzees after single doses of chimpanzee, human, or human-pegylated IFN-␣. Liver and peripheral blood mononuclear cell (PBMC) samples were used for total genome microarray analysis. Most induced genes achieved maximal response within 4 hours, began to decline by 8 hours, and were at baseline levels by 24 hours postinoculation, a time when high levels of circulating pegylated IFN-␣ were still present. W orldwide, approximately 170 million people are chronically infected with hepatitis C virus (HCV), which frequently progresses to serious liver disease, including cirrhosis and hepatocellular carcinoma. 1,2 The current therapy involves the combination of pegylated (peg)-interferon alpha (IFN-␣) and ribavirin (reviewed in Feld and Hoofnagle 3 ) and has response rates for sustained viral clearance of approximately 40% to 50% and 80% to 90% for genotypes 1 and 2/3, respectively. 4,5 However, a significant proportion of the population still develops serious disease as a consequence of HCV infection. HCV infection is the leading cause for liver transplantation in the United States 1,2 and liver cancer due to HCV infection is one of the most rapidly increasing types of cancer in the United States. 6 Little is understood regarding the factors leading to successful or failed viral clearance during IFN-␣ therapy. The early kinetics of viral RNA loss from the circulation during IFN-␣ therapy suggests the presence of two phases. Phase I occurs during the first 24 to 48 hours and is presumed to be due to the decrease in secretion of new virions, whereas phase II kinetics vary between individuals, are predictive of the outcome of therapy, and are thought to be a measurement of loss of infected cells. [7][8][9] We 10,11 and others 12 have previously performed gene expression analyses on liver from chimpanzees that experienced acute-resolving or chronic HCV infections. The

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Section: Discussionmentioning

confidence: 99%

Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

et al. 2006

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“…Accordingly, T cell activation and differentiation is also regulated by SOCS1 (15,16). Besides regulating IFN-␥ signaling, SOCS1 is crucial in attenuating STAT1-mediated IFN-␣/␤ signaling (17) and has also been shown to attenuate IL-12 (18), , and other ␥ c -dependent cytokine (20) signaling in myeloid and lymphoid cells.…”

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confidence: 99%

Silencing Suppressor of Cytokine Signaling-1 (SOCS1) in Macrophages Improves Mycobacterium tuberculosis Control in an Interferon-γ (IFN-γ)-dependent Manner

Carow

Gavier‐Widén

et al. 2011

Journal of Biological Chemistry

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“…has been previously described (27)(28)(29). Mice homozygous null for the Ifnar2gene have previously been generated (30) and were crossed with gp130 F/F mice to generate the compound mutant gp130 …”

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confidence: 99%

IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3

Greenhill

Rose-John

Lissilaa

et al. 2011

The Journal of Immunology

237

159

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Innate immune responses triggered by the prototypical inflammatory stimulus LPS are mediated by TLR4 and involve the coordinated production of a multitude of inflammatory mediators, especially IL-6, which signals via the shared IL-6 cytokine family receptor subunit gp130. However, the exact role of IL-6, which can elicit either proinflammatory or anti-inflammatory responses, in the pathogenesis of TLR4-driven inflammatory disorders, as well as the identity of signaling pathways activated by IL-6 in a proinflammatory state, remain unclear. To define the contribution of gp130 signaling events to TLR4-driven inflammatory responses, we combined genetic and therapeutic approaches based on a series of gp130F/F knock-in mutant mice displaying hyperactivated IL-6–dependent JAK/STAT signaling in an experimental model of LPS/TLR4-mediated septic shock. The gp130F/F mice were markedly hypersensitive to LPS, which was associated with the specific upregulated production of IL-6, but not TNF-α. In gp130F/F mice, either genetic ablation of IL-6, Ab-mediated inhibition of IL-6R signaling or therapeutic blockade of IL-6 trans-signaling completely protected mice from LPS hypersensitivity. Furthermore, genetic reduction of STAT3 activity in gp130F/F:Stat3+/− mice alleviated LPS hypersensitivity and reduced LPS-induced IL-6 production. Additional genetic approaches demonstrated that the TLR4/Mal pathway contributed to LPS hypersensitivity and increased IL-6 production in gp130F/F mice. Collectively, these data demonstrate for the first time, to our knowledge, that IL-6 trans-signaling via STAT3 is a critical modulator of LPS-driven proinflammatory responses through cross-talk regulation of the TLR4/Mal signaling pathway, and potentially implicate cross-talk between JAK/STAT and TLR pathways as a broader mechanism that regulates the severity of the host inflammatory response.

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Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity

Cited by 250 publications

References 51 publications

Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

Silencing Suppressor of Cytokine Signaling-1 (SOCS1) in Macrophages Improves Mycobacterium tuberculosis Control in an Interferon-γ (IFN-γ)-dependent Manner

IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3

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