Nature Immunology
4, 540 - 545 (2003)
Published online: 18 May 2003; | doi:10.1038/ni931
SOCS3 negatively regulates IL-6 signaling in vivoBen A Croker1, Danielle L Krebs1, Jian-Guo Zhang1, Sam Wormald1, Tracy A Willson1, Edouard G Stanley2, Lorraine Robb1, Christopher J Greenhalgh1, Irmgard Förster3, Björn E Clausen4, Nicos A Nicola1, Donald Metcalf1, Douglas J Hilton1, Andrew W Roberts1
& Warren S Alexander11
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, Victoria 3050, Australia. 2
Monash Institute for Reproduction and Development, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. 3
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstrasse 4b, D-81675 Munich, Germany. 4
Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Room L3-354, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Correspondence should be addressed to Warren S Alexander alexandw@wehi.edu.auMembers 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- (IFN-). Conversely, IL-6-induced STAT activation is normal in Socs1-deficient cells, whereas STAT1 activation induced by IFN- is prolonged. Microarray analysis shows that the pattern of gene expression induced by IL-6 in Socs3-deficient livers mimics that induced by IFN-. Our data indicate that SOCS3 and SOCS1 have reciprocal functions in IL-6 and IFN- regulation and imply that SOCS3 has a role in preventing IFN--like responses in cells stimulated by IL-6.
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