Excess IL-1 signaling enhances the development of Th17 cells by downregulating TGF-β-induced Foxp3 expression

J Immunol. 2014 Feb 15;192(4):1449-58. doi: 10.4049/jimmunol.1300387. Epub 2014 Jan 15.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Animals
  • Arthritis, Rheumatoid / immunology*
  • Basic-Leucine Zipper Transcription Factors / biosynthesis
  • Cell Differentiation
  • Cells, Cultured
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / metabolism*
  • Interleukin 1 Receptor Antagonist Protein / deficiency
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Interleukin-1 / metabolism*
  • Interleukin-17 / metabolism
  • Interleukin-6 / deficiency
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Interleukins / biosynthesis
  • Interleukins / metabolism
  • Lymph Nodes / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / biosynthesis
  • Receptors, Interleukin-1 Type I / antagonists & inhibitors
  • Signal Transduction
  • Th17 Cells / metabolism*
  • Transforming Growth Factor beta / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Basic-Leucine Zipper Transcription Factors
  • Batf protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • IL1R1 protein, mouse
  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Interleukin-17
  • Interleukin-6
  • Interleukins
  • Nfkbiz protein, mouse
  • Nuclear Proteins
  • Receptors, Interleukin-1 Type I
  • Transforming Growth Factor beta
  • interleukin-21