Fos proteins suppress dextran sulfate sodium-induced colitis through inhibition of NF-kappaB.
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.
Takada
Yasunari
Y
Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.
Ray
Neelanjan
N
Ikeda
Eiji
E
Kawaguchi
Tomohiro
T
Kuwahara
Masayoshi
M
Wagner
Erwin F
EF
Matsuo
Koichi
K
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000494:pharmacology; D007249:Inflammation / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099169:Fos-Related Antigen 1
D016207:Cytokines; D016264:Dextran Sulfate; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000099169:Fos-Related Antigen 1