title: Excess IL-1 signaling enhances the development of Th17 cells by downregulating TGF-β-induced Foxp3 expression.
abstract: IL-1R antagonist-deficient (Il1rn(-/-)) mice develop autoimmune arthritis in which IL-17A plays a crucial role. Although many studies have shown that Th17 cell differentiation is dependent on TGF-β and IL-6, we found that Th17 cells developed normally in Il1rn(-/-)Il6(-/-) mice in vivo. Then, we analyzed the mechanisms of Th17 cell differentiation in Il1rn(-/-)Il6(-/-) mice. We found that IL-21 production was increased in the lymph nodes of Il1rn(-/-) mice, naive Il6(-/-) CD4(+) T cells differentiated into Th17 cells when cultured with TGF-β and IL-21, and the differentiation was greatly enhanced when IL-1 was added to the culture. Th17 cell differentiation was not induced by either TGF-β or IL-1 alone or in combination. IL-21 induced IL-1R expression in naive CD4(+) T cells, and IL-1 inhibited TGF-β-induced Foxp3 expression, resulting in the promotion of Th17 cell differentiation. Furthermore, IL-1 augmented the expression of Th17 cell-specific transcription factors such as Nfkbiz and Batf. These results indicate that excess IL-1 signaling can overcome the requirement of IL-6 in the differentiation of Th17 cells by suppressing Foxp3 expression and inducing Th17 cell-specific transcription factors.
authors.affiliation: Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ikeda
authors.forename: Shinobu
authors.initials: S
authors.lastname: Saijo
authors.forename: Masanori A
authors.initials: MA
authors.lastname: Murayama
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimizu
authors.forename: Aoi
authors.initials: A
authors.lastname: Akitsu
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis; D002454:Cell Differentiation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency / Q000235:genetics; D007375:Interleukin-1 / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000096:biosynthesis / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D058504:Th17 Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050976:Basic-Leucine Zipper Transcription Factors; C431772:Batf protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C583355:IL1R1 protein, mouse; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D053573:Receptors, Interleukin-1 Type I; D016212:Transforming Growth Factor beta; D000098546:Interleukin-21