SOCS3 regulates the plasticity of gp130 signaling
Abstract
Suppressor of cytokine signaling (SOCS) proteins are feedback inhibitors of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathway. SOCS3 is upregulated by several signals in macrophages and has been implicated as a regulator of various signaling pathways. Here we show that phosphorylation of STAT3 is prolonged in mouse Socs3-deficient macrophages after stimulation with interleukin-6 (IL-6) but not IL-10, indicating that SOCS3 specifically affects signaling mediated by IL-6 and gp130. IL-6 induces a wider transcriptional response in Socs3-deficient macrophages than in wild-type cells; this response is dominated by interferon (IFN)-regulated genes owing to an excess of STAT1 phosphorylation. Thus, SOCS3 functions to control the quality of the response to IL-6 and prevents the activation of an IFN-induced program of gene expression.
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IL-6 signaling in the absence of SOCS3 resulted in prolonged phosphorylation of STAT1 and a qualitative shift in the transcriptional response of IL-6 toward that typical of IFNγ.
“Surprisingly, IL-6 signaling in the absence of SOCS3 resulted in the prolonged phosphorylation of STAT1 and a qualitative shift in the transcriptional response of IL-6 toward that typical of IFN␥ (16,24,25).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [25]
Mice conditionally deficient for Socs3 revealed SOCS3 to be a potent physiological suppressor of IL-6 but not IFNγ signaling.
“the generation of mice conditionally deficient for Socs3 revealed SOCS3 to be a potent physiological suppressor of IL-6 but not IFN␥ signaling (24 -26).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [25]
Signaling by IFNγ and IL-6 is fundamentally similar, and activity of SOCS3 is required to sculpt the cellular response to IL-6 and thereby discriminate it from that of IFNγ.
“This indicates that signaling by IFN␥ and IL-6 is fundamentally similar, and that the activity of SOCS3 is required to sculpt the cellular response to IL-6 and thereby discriminate it from that of IFN␥.”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [25]
Each of these stimuli activates the glycoprotein-130/STAT3 or G-CSF-receptor/STAT3 signaling pathways, which are known to be inhibited by SOCS3 in vivo.
“Interestingly, each of these stimuli activates the glycoprotein-130/STAT3 or the granulocytecolony stimulating factor-receptor/STAT3 signaling pathways, which are known to be inhibited by SOCS3 in vivo (24 -26, 29, 40, 41).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [25]
Despite the physiologically distinct functions of IFNγ and IL-6, the signaling mechanisms by which they elicit cellular responses are similar, and in the case of IL-6 are distinguished at least in part through the activity of SOCS3.
“Despite the physiologically distinct functions of IFN␥ and IL-6, the signaling mechanisms by which they elicit their cellular responses are similar, and in the case of IL-6 are distinguished at least in part through the activity of SOCS3 (16,24,25).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [25]
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- Authors
- Lang, R., Pauleau, A.-L., Parganas, E., Takahashi, Y., Mages, J., Ihle, J. N., Rutschman, R., & Murray, P. J.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Centre National de la Recherche Scientifique (FR)
- Technical University of Munich (DE)
- Corresponding author
- Murray, Peter J
- Venue
- Nature Immunology
- Published
- 2003-05-18
- Volume
- 4
- Issue
- 6
- Pages
- 546-550
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W1972363513
- Cited by
- 439
- References
- 3
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 10 · 2023: 11 · 2022: 7 · 2021: 7 · 2020: 10 · 2019: 18 · 2018: 9 · 2017: 16 · 2016: 22 · 2015: 10 · 2014: 21 · 2013: 21 · 2012: 17
- FWCI
- 18.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- American Heart Association
- American Lebanese Syrian Associated Charities
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (5r03ai053478-02)
- National Cancer Institute (P 30CA 21765, P30CA021765)
- National Institute of Allergy and Infectious Diseases (AI53478-01)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- SOCS3, gp130 signaling, interleukin-6, STAT3 phosphorylation, STAT1 phosphorylation, macrophages, interferon-regulated genes, transcriptional response
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, DNA-Binding Proteins, Female, Interferon-gamma, Macrophages, Male, Membrane Glycoproteins, Phosphorylation, Proteins, Repressor Proteins, Transcription Factors, Signal Transduction, Trans-Activators, Antigens, CD, Interleukin-6, Interleukin-10, Mice, Knockout, src Homology Domains, Oligonucleotide Array Sequence Analysis, STAT1 Transcription Factor, STAT3 Transcription Factor, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Mice
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