Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1-dependent pathway

被引:192
作者
Hegazi, RAF
Rao, KN
Mayle, A
Sepulveda, AR
Otterbein, LE
Plevy, SE [1 ]
机构
[1] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA 15261 USA
[3] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA
[4] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02115 USA
关键词
D O I
10.1084/jem.20051047
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Heme oxygenase (HO)-1 and its metabolic product carbon monoxide ( CO) play regulatory roles in acute inflammatory states. In this study, we demonstrate that CO administration is effective as a therapeutic modality in mice with established chronic colitis. CO administration ameliorates chronic intestinal inflammation in a T helper (Th)1-mediated model of murine colitis, interleukin (IL)-10-deficient (IL-10(-/-)) mice. In Th1-mediated inflammation, CO abrogates the synergistic effect of interferon (IFN)-gamma on lipopolysaccharide-induced IL-12 p40 in murine macrophages and alters IFN-gamma signaling by inhibiting a member of the IFN regulatory factor (IRF) family of transcription factors, IRF-8. A specific signaling pathway, not previously identified, is delineated that involves an obligatory role for HO-1 induction in the protection afforded by CO. Moreover, CO antagonizes the inhibitory effect of IFN-gamma on HO-1 expression in macrophages. In macrophages and in Th1-mediated colitis, pharmacologic induction of HO-1 recapitulates the immunosuppressive effects of CO. In conclusion, this study begins to elucidate potential etiologic and therapeutic implications of CO and the HO-1 pathway in chronic inflammatory bowel diseases.
引用
收藏
页码:1703 / 1713
页数:11
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