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PMID: 16365149 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The Journal of experimental medicine ·Vol. 202 ·No. 12 ·2005-12-19 ·Pages 1703-13

Hegazi RA, Rao KN, Mayle A, Sepulveda AR, Otterbein LE, Plevy SE

Abstract

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.

MeSH Terms
Administration, Inhalation Animals Carbon Monoxide/administration & dosage,metabolism,therapeutic use Colitis/drug therapy,immunology DNA Primers Enzyme Induction/drug effects Enzyme-Linked Immunosorbent Assay Heme Oxygenase-1/biosynthesis,metabolism Interferon Regulatory Factors/metabolism Interferon-gamma/antagonists & inhibitors Interleukin-10/genetics Mice Mice, Knockout Models, Biological Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/immunology Th1 Cells/immunology
Chemicals
DNA Primers Interferon Regulatory Factors interferon regulatory factor-8 Interleukin-10 Carbon Monoxide Interferon-gamma Heme Oxygenase-1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Hegazi Refaat A F
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Rao Kavitha N
Mayle Aqila
Sepulveda Antonia R
Otterbein Leo E
Plevy Scott E
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20051047
Published
2005-12-19
Pages
1703-13
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2212966
Subset
IM
Grants
NIDDK NIH HHS · R01 DK054452 · United States
NHLBI NIH HHS · R01 HL071797 · United States
External Links
PubMed source DOI: 10.1084/jem.20051047 PMC Full Text View journal details
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