Negative regulation of interleukin-12 signaling by suppressor of cytokine signaling-1.
Suppressor of cytokine signaling-1 (SOCS-1) is an inhibitory protein that regulates responses to cytokines. Previously, we have shown SOCS-1 to be a key inhibitor of interferon gamma (IFNgamma). Recent data suggest that SOCS-1 may regulate other cytokines in vivo, in addition to IFNgamma. Uncontrolled responses to interleukin-12 (IL-12), an inflammatory cytokine, could contribute to increased IFNgamma production and the development of inflammatory disease in SOCS-1(-/-) mice. Here, we assess responses of SOCS-1-deficient cells to IL-12. Both IL-12-induced T cell proliferation and NK cytotoxic activity are enhanced in SOCS-1-deficient cells, relative to controls. To examine the contribution of continued IL-12 signaling to the SOCS-1(-/-) disease, we generated mice lacking both SOCS-1 and signal transducer and activator of transcription 4 (STAT4), an essential component of the IL-12 signaling pathway. SOCS-1(-/-) STAT4(-/-) mice have improved survival relative to SOCS-1(-/-) mice, but die between 1 and 2 months of age. We conclude that, in addition to IFNgamma, SOCS-1 regulates responses to IL-12.
Eyles
Joanne L
JL
The Walter and Eliza Hall Institute for Medical Research and The Cooperative Research Center for Cellular Growth Factors, PO Royal Melbourne Hospital, VIC 3050, Australia.
Metcalf
Donald
D
Grusby
Michael J
MJ
Hilton
Douglas J
DJ
Starr
Robyn
R
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D012097:Repressor Proteins; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D012097:Repressor Proteins; D050797:STAT4 Transcription Factor; C491590:Socs1 protein, mouse; C494091:Stat4 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma