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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / biosynthesis
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Animals
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Arthritis, Rheumatoid / immunology*
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Basic-Leucine Zipper Transcription Factors / biosynthesis
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Cell Differentiation
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Cells, Cultured
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Forkhead Transcription Factors / biosynthesis
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Forkhead Transcription Factors / metabolism*
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Interleukin 1 Receptor Antagonist Protein / deficiency
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Interleukin 1 Receptor Antagonist Protein / genetics
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Interleukin-1 / metabolism*
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Interleukin-17 / metabolism
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Interleukin-6 / deficiency
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Interleukin-6 / genetics
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Interleukin-6 / metabolism*
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Interleukins / biosynthesis
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Interleukins / metabolism
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Lymph Nodes / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Nuclear Proteins / biosynthesis
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Receptors, Interleukin-1 Type I / antagonists & inhibitors
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Signal Transduction
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Th17 Cells / metabolism*
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Transforming Growth Factor beta / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Basic-Leucine Zipper Transcription Factors
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Batf protein, mouse
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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IL1R1 protein, mouse
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Il1rn protein, mouse
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-1
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Interleukin-17
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Interleukin-6
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Interleukins
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Nfkbiz protein, mouse
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Nuclear Proteins
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Receptors, Interleukin-1 Type I
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Transforming Growth Factor beta
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interleukin-21