TGF-beta 1 inhibition of IFN-gamma-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent.
In addition to classic Smad signaling pathways, the pleiotropic immunoregulatory cytokine TGF-beta1 can activate MAP kinases, but a role for TGF-beta1-MAP kinase pathways in T cells has not been defined heretofore. We have shown previously that TGF-beta1 inhibits Th1 development by inhibiting IFN-gamma's induction of T-bet and other Th1 differentiation genes, and that TGF-beta1 inhibits receptor-proximal IFN-gamma-Jak-Stat signaling responses. We now show that these effects of TGF-beta1 are independent of the canonical TGF-beta1 signaling module Smad3, but involve a specific MAP kinase pathway. In primary T cells, TGF-beta1 activated the MEK/ERK and p38 MAP kinase pathways, but not the JNK pathway. Inhibition of the MEK/ERK pathway completely eliminated the inhibitory effects of TGF-beta1 on IFN-gamma responses in T cells, whereas inhibition of the p38 pathway had no effect. Thus, TGF-beta1's inhibition of IFN-gamma signaling in T cells is mediated through a highly specific Smad3 independent, MEK/ERK-dependent signaling pathway.
Park
Il-Kyoo
IK
Department of Pathology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA.
Letterio
John J
JJ
Gorham
James D
JD
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018417:Th1 Cells / Q000201:enzymology* / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases