Fos Proteins Suppress Dextran Sulfate Sodium-Induced Colitis through Inhibition of NF-kappa B

作者：Takada Yasunari; Ray Neelanjan; Ikeda Eiji; Kawaguchi Tomohiro; Kuwahara Masayoshi; Wagner Erwin F; Matsuo Koichi^*

来源：The Journal of Immunology, 2010, 184(2): 1014-1021.

DOI：10.4049/jimmunol.0901196

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-kappa B activity in colon segments of DSS-treated Fos(-/-) mice. Furthermore, NF-kappa B 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-kappa B 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-kappa B 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-kappa B 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-kappa B-mediated stress responses. The Journal of Immunology, 2010, 184: 1014-1021.

• 出版日期2010-1-15