TGF-beta is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23.
TGF-beta and IL-6 induce Th17 differentiation, and IL-23 is required for expansion and maintenance of Th17 cells. Recently, it was shown that IL-6 up-regulates IL-23R mRNA in naive CD4+ T cells and therefore IL-6 and IL-23 synergistically promote Th17 differentiation. However, the molecular mechanism whereby IL-6 and IL-23 induce Th17 differentiation and the relevance to TGF-beta remain unknown. Here, we found that IL-6 up-regulated IL-23R mRNA expression, and IL-6 and IL-23 synergistically augmented its protein expression. The combination induced Th17 differentiation, and TGF-beta1 further enhanced it. IL-6 augmented endogenous TGF-beta1 mRNA expression, whereas the amount of TGF-beta produced was not enough to induce Th17 differentiation by IL-6 alone. However, unexpectedly, the up-regulation of IL-23R and induction of Th17 differentiation by IL-6 and IL-23 were almost completely inhibited by anti-TGF-beta. These results suggest that the induction of IL-23R and Th17 differentiation by IL-6 and IL-23 is mediated through endogenously produced TGF-beta.
Morishima
Noriko
N
Intractable Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
Mizoguchi
Izuru
I
Takeda
Kiyoshi
K
Mizuguchi
Junichiro
J
Yoshimoto
Takayuki
T
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D016212:Transforming Growth Factor beta; C528688:interleukin-23 receptor, mouse