Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1-dependent pathway.
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.
Hegazi
Refaat A F
RA
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Rao
Kavitha N
KN
Mayle
Aqila
A
Sepulveda
Antonia R
AR
Otterbein
Leo E
LE
Plevy
Scott E
SE
D000280:Administration, Inhalation; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology; D017931:DNA Primers; D004790:Enzyme Induction / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D016753:Interleukin-10 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D000099185:Interferon Regulatory Factor-8
D002248:Carbon Monoxide; D017931:DNA Primers; D051547:Heme Oxygenase-1; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D016753:Interleukin-10; D000099185:Interferon Regulatory Factor-8