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SOCS3 negatively regulates IL-6 signaling in vivo

Nature Immunology volume 4, pages 540–545 (2003)Cite this article

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-γ (IFN-γ). Conversely, IL-6-induced STAT activation is normal in Socs1-deficient cells, whereas STAT1 activation induced by IFN-γ is prolonged. Microarray analysis shows that the pattern of gene expression induced by IL-6 in Socs3-deficient livers mimics that induced by IFN-γ. Our data indicate that SOCS3 and SOCS1 have reciprocal functions in IL-6 and IFN-γ regulation and imply that SOCS3 has a role in preventing IFN-γ-like responses in cells stimulated by IL-6.

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Figure 1: Conditional targeting of the Socs3 gene.
Figure 2: IL-6-induced phosphorylation of STAT3 and STAT1.
Figure 3: Regulation of IL-6 and IFN-γ signaling in Socs3- and Socs1-deficient cells.
Figure 4: IL-6 induces the expression of IFN-γ-inducible genes in the absence of Socs3.
Figure 5: Socs3-deficient macrophages are hyperresponsive to IL-6.

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Acknowledgements

We thank D. LeRoith for providing the Alb-cre transgenic mice; G. Panoschi for animal husbandry; S. Cane and J. Mighall for genotyping; and A. Steptoe, L. Hartley and T. Speed for technical assistance. This work was supported by the Australian National Health and Medical Research Council (Program Grant 257500); US National Institutes of Health Grant CA22556; the Cancer Council of Victoria Carden Fellowship (to D.M.) and the Sir Edward Dunlop Clinical Fellowship (to A.W.R.); and AMRAD Operations Pty Ltd.

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Authors and Affiliations

  1. Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, 1G Royal Parade, Parkville, 3050, Victoria, Australia

    Ben A Croker, Danielle L Krebs, Jian-Guo Zhang, Sam Wormald, Tracy A Willson, Lorraine Robb, Christopher J Greenhalgh, Nicos A Nicola, Donald Metcalf, Douglas J Hilton, Andrew W Roberts & Warren S Alexander

  2. Monash Institute for Reproduction and Development, Monash Medical Centre, 246 Clayton Road, Clayton, 3168, Victoria, Australia

    Edouard G Stanley

  3. Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstrasse 4b, Munich, D-81675, Germany

    Irmgard Förster

  4. Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Room L3-354, Meibergdreef 15, Amsterdam, 1105, AZ, The Netherlands

    Björn E Clausen

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Correspondence to Warren S Alexander.

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N.N. and D.J.H. work as consultants for AMRAD Operations Pty Ltd. This company provided support for the work described in this paper.

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Croker, B., Krebs, D., Zhang, JG. et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 4, 540–545 (2003). https://doi.org/10.1038/ni931

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