Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1.
Interleukin 6 (IL-6) is a cytokine produced by immune and nonimmune cells and exhibits functional pleiotropy and redundancy. IL-6 plays an important role in the differentiation of several cell types. Here, we describe a novel function of IL-6: the negative regulation of CD4+ Th1 cell differentiation. While IL-6-directed CD4+ Th2 differentiation is mediated by IL-4, inhibition of Th1 differentiation by IL-6 is independent of IL-4. IL-6 upregulates suppressor of cytokine signaling 1 (SOCS1) expression in activated CD4+ T cells, thereby interfering with signal transducer and activator of transcription 1 (STAT1) phosphorylation induced by interferon gamma (IFNgamma). Inhibition of IFNgamma receptor-mediated signals by IL-6 prevents autoregulation of IFNgamma gene expression by IFNgamma during CD4+ T cell activation, thereby preventing Th1 differentiation. Thus, IL-6 promotes CD4+ Th2 differentiation and inhibits Th1 differentiation by two independent molecular mechanisms.
Diehl
Sean
S
Department of Medicine, University of Vermont, Burlington 05405, USA.
Anguita
J
J
Hoffmeyer
A
A
Zapton
T
T
Ihle
J N
JN
Fikrig
E
E
Rincón
M
M
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D017471:Receptors, Interferon / Q000378:metabolism; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018417:Th1 Cells / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation; D000096743:Interferon gamma Receptor
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D018664:Interleukin-12; D015847:Interleukin-4; D015850:Interleukin-6; D017471:Receptors, Interferon; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse