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

J Immunol. 2010 Jan 15;184(2):1014-21. doi: 10.4049/jimmunol.0901196. Epub 2009 Dec 16.


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-alpha production and NF-kappaB activity in colon segments of DSS-treated Fos(-/-) mice. Furthermore, NF-kappaB 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-kappaB 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-kappaB 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-kappaB 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-kappaB-mediated stress responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / chemically induced
  • Colitis / prevention & control*
  • Cytokines / biosynthesis
  • Dextran Sulfate / pharmacology
  • Inflammation / prevention & control
  • Mice
  • Mice, Transgenic
  • NF-kappa B / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / physiology*
  • Stress, Physiological
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Cytokines
  • NF-kappa B
  • Proto-Oncogene Proteins c-fos
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • fos-related antigen 1
  • Dextran Sulfate