The two faces of IL-6 on Th1/Th2 differentiation.
Interleukin (IL)-6 is a cytokine produced by several cell types including antigen presenting cells (APC) such as macrophages, dendritic cells, and B cells. IL-6 is involved in the acute phase response, B cell maturation, and macrophage differentiation. Here, we discuss a novel function of IL-6: the control of T helper (Th) 1/Th2 differentiation. IL-6 promotes Th2 differentiation and simultaneously inhibits Th1 polarization through two independent molecular mechanisms. IL-6 activates transcription mediated by nuclear factor of activated T cells (NFAT) leading to production of IL-4 by nai;ve CD4(+) T cells and their differentiation into effector Th2 cells. While the induction of Th2 differentiation by IL-6 is dependent upon endogenous IL-4, inhibition of Th1 differentiation by IL-6 is IL-4- and NFAT-independent. IL-6 inhibits Th1 differentiation by upregulating supressor of cytokine signaling (SOCS)-1 expression to interfere with IFNgamma signaling and the development of Th1 cells. Since IL-6 is abundantly produced by APC, it is a likely source of early Th1/Th2 control during CD4(+) T cell activation. Thus, by using two independent molecular mechanisms, IL-6 plays a dual role in Th1/Th2 differentiation.
Diehl
Sean
S
Immunobiology Program, Department of Medicine, University of Vermont, Given Medical Building D305, Burlington, VT 05405, USA. mrincon@zoo.uvm.edu
Rincón
Mercedes
M
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis; D002454:Cell Differentiation; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D018448:Models, Immunological; D012097:Repressor Proteins; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D015533:Transcriptional Activation
D002352:Carrier Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015847:Interleukin-4; D007371:Interferon-gamma