SOCS1-negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes

Xiuju Dai, Koji Sayama, Kenshi Yamasaki, Mikiko Tohyama, Yuji Shirakata, Yasushi Hanakawa, Sho Tokumaru, Yoko Yahata, Lujun Yang, Akihiko Yoshimura, Koji Hashimoto

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54 Citations (Scopus)

Abstract

Toll-like receptor (TLR)3 is a receptor for virus-associated double-stranded RNA, and triggers antiviral immune responses during viral infection. Epidermal keratinocytes express TLR3 and provide an innate immune defense against viral infection. Since the intracellular regulatory mechanism is unknown, we hypothesized that the signal transducers and activators of transcription (STAT)-suppressors of cytokine signaling (SOCS) system regulates the innate immune response of keratinocytes. Treatment with polyinosinic- polycytidylic acid (poly(I:C)) resulted in the rapid translocation of IFN regulatory factor (IRF)-3 into the nucleus, followed by phosphorylation of STAT1 and STAT3. The activation of STATs by poly(I:C) probably occurs in an indirect fashion, through poly(I:C)-induced IFN. We infected cells with the dominant-negative forms of STAT1 (STAT1F), STAT3 (STAT3F), and SOCS1 using adenovirus vectors. Infection with STAT1F suppressed the induction of macrophage inflammatory protein (MIP)-1α by poly(I:C), whereas STAT3F had a minimal effect, which indicates that STAT1 mediates MIP-1α induction. SOCS1, which is a negative feedback regulator of STAT1 signaling, was induced by treatment with poly(I:C). SOCS1 infection inhibited the phosphorylation of STAT1 and significantly reduced poly(I:C)-induced MIP-1α production. Furthermore, STAT1-SOCS1 regulated poly(I:C)-induced TLR3 and IRF-7 expression. However, SOCS1 did not affect NF-κB signaling. Thus, the STAT1-SOCS1 pathway regulates the innate immune response via TLR3 signaling in epidermal keratinocytes.

Original languageEnglish
Pages (from-to)1574-1581
Number of pages8
JournalJournal of Investigative Dermatology
Volume126
Issue number7
DOIs
Publication statusPublished - 2006 Jul
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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    Dai, X., Sayama, K., Yamasaki, K., Tohyama, M., Shirakata, Y., Hanakawa, Y., Tokumaru, S., Yahata, Y., Yang, L., Yoshimura, A., & Hashimoto, K. (2006). SOCS1-negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes. Journal of Investigative Dermatology, 126(7), 1574-1581. https://doi.org/10.1038/sj.jid.5700294