Fos proteins suppress dextran sulfate sodium-induced colitis through inhibition of NF-κB

Yasunari Takada, Neelanjan Ray, Eiji Ikeda, Tomohiro Kawaguchi, Masayoshi Kuwahara, Erwin F. Wagner, Koichi Matsuo

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The Fos family proteins, c-Fos and Fra-1, are components of the dimeric transcription factor AP-1, which is typically composed of Fos and Jun family proteins. We have previously shown that mice lacking c-Fos (Fos-/- mice) respond more strongly to LPS injection than do wild-type (wt) controls.We then examined the sensitivity of Fos-/- mice to acute inflammatory stress in a dextran sulfate sodium (DSS)-induced colitis model. We found that Fos -/- mice exhibited more severe weight loss, bleeding, diarrhea, and colon shortening than did wt mice, in association with higher TNF-α production and NF-κB activity in colon segments of DSS-treated Fos -/- mice. Furthermore, NF-κB inhibition suppressed severe DSS-induced colitis in Fos-/- mice. In contrast, Fra-1 transgenic (Tg) mice responded poorly to LPS injection, and Fra-1-overexpressing macrophages and fibroblasts showed reduced production of proinflammatory cytokines, NO, and NF-κB activity. Remarkably, in the DSS-induced colitis model, Fra-1 Tg mice showed less severe clinical scores of colitis than did wt mice. Consistently, proinflammatory cytokine production and NF-κB activity in colon segments of DSS-treated Fra-1 Tg mice were lower than in wt controls. These findings reveal that the absence of c-Fos and overexpression of Fra-1 respectively enhance and suppress the activation of NF-κB in DSS-induced inflammatory stress. In this paper, we propose that AP-1 transcription factors containing c-Fos or Fra-1 are negative regulators of NF-κB-mediated stress responses.

Original languageEnglish
Pages (from-to)1014-1021
Number of pages8
JournalJournal of Immunology
Issue number2
Publication statusPublished - 2010 Jan 15


ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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