SOCS3 negatively regulates IL-6 signaling in vivo
Abstract
Members of the suppressor of cytokine signaling (SOCS) family are potentially key physiological negative regulators of interleukin-6 (IL-6) signaling. To examine whether SOCS3 is involved in regulating this signaling, we have used conditional gene targeting to generate mice lacking Socs3 in the liver or in macrophages. We show that Socs3 deficiency results in prolonged activation of signal transducer and activator of transcription 1 (STAT1) and STAT3 after IL-6 stimulation but normal activation of STAT1 after stimulation with interferon-gamma (IFN-gamma). Conversely, IL-6-induced STAT activation is normal in Socs1-deficient cells, whereas STAT1 activation induced by IFN-gamma is prolonged. Microarray analysis shows that the pattern of gene expression induced by IL-6 in Socs3-deficient livers mimics that induced by IFN-gamma. Our data indicate that SOCS3 and SOCS1 have reciprocal functions in IL-6 and IFN-gamma regulation and imply that SOCS3 has a role in preventing IFN-gamma-like responses in cells stimulated by IL-6.
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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 [24]
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 [24]
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 [24]
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 [24]
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 [24]
SOCS3 is a negative regulator of IL-6 signaling.
“STAT3 inducible SOCS3 is part of a negative feedback loop that inhibits IL-6 signaling, i.e. STAT3 phosphorylation (30).”
From A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals (2013) · cites this paper as [30]
SOCS-3 negatively regulates IL-6 signaling in vivo.
“It has been shown that SOCS-3 negatively regulates IL-6 signaling in vivo (43).”
From The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury (2005) · cites this paper as [43]
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- Authors
- Croker, B. A., Krebs, D. L., Zhang, J.-G., Wormald, S., Willson, T. A., Stanley, E. G., Robb, L., Greenhalgh, C. J., Förster, I., Clausen, B. E., Nicola, N. A., Metcalf, D., Hilton, D. J., Roberts, A. W., & Alexander, W. S.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- Monash Medical Centre (AU)
- Technical University of Munich (DE)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Alexander, Warren S
- ORCID
- Venue
- Nature Immunology
- Published
- 2003-05-18
- Volume
- 4
- Issue
- 6
- Pages
- 540-545
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2147495692
- Cited by
- 840
- References
- 4
- Citations by year
- 2026: 23 · 2025: 17 · 2024: 26 · 2023: 25 · 2022: 14 · 2021: 45 · 2020: 31 · 2019: 39 · 2018: 32 · 2017: 33 · 2016: 43 · 2015: 24 · 2014: 38 · 2013: 42 · 2012: 54
- FWCI
- 23.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Chinese Academy of Agricultural Sciences
- National Cancer Institute (CA22556)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- SOCS3, SOCS1, IL-6 signaling, STAT1 activation, STAT3 activation, interferon-gamma signaling, negative regulation of cytokine signaling, liver, macrophages, conditional gene targeting, gene expression profiling
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Animals, Carrier Proteins, DNA-Binding Proteins, Female, Interferon-gamma, Liver, Macrophages, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Phosphorylation, Proteins, Repressor Proteins, Transcription Factors, Transcription, Genetic, Signal Transduction, Trans-Activators, Interleukin-6, Polymerase Chain Reaction, Interleukin-10, Mice, Knockout, Oligonucleotide Array Sequence Analysis, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice
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