Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation.
Interleukin (IL)-6 is produced by professional antigen-presenting cells (APCs) such as B cells, macrophages, and dendritic cells. It has been previously shown that APC-derived IL-6 promotes the differentiation of naive CD4+ T cells into effector T helper type 2 (Th2) cells. Here, we have studied the molecular mechanism for IL-6-mediated Th2 differentiation. During the activation of CD4+ T cells, IL-6 induces the production of IL-4, which promotes the differentiation of these cells into effector Th2 cells. Regulation of IL-4 gene expression by IL-6 is mediated by nuclear factor of activated T cells (NFAT), as inhibition of NFAT prevents IL-6-driven IL-4 production and Th2 differentiation. IL-6 upregulates NFAT transcriptional activity by increasing the levels of NFATc2. The ability of IL-6 to promote Th2 differentiation is impaired in CD4+ T cells that lack NFATc2, demonstrating that NFATc2 is required for regulation of IL-4 gene expression by IL-6. Regulation of NFATc2 expression and NFAT transcriptional activity represents a novel pathway by which IL-6 can modulate gene expression.
Diehl
Sean
S
Immunobiology Program, Department of Medicine, Given Medical Building, University of Vermont, Burlington, VT 05405, USA.
Chow
Chi-Wing
CW
Weiss
Linda
L
Palmetshofer
Alois
A
Twardzik
Thomas
T
Rounds
Laura
L
Serfling
Edgar
E
Davis
Roger J
RJ
Anguita
Juan
J
Rincón
Mercedes
M
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D005799:Genes, Dominant; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C494007:Nfatc2 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D015847:Interleukin-4