Cutting edge: IFN-gamma is a negative regulator of IL-23 in murine macrophages and experimental colitis.
IL-23 regulation is a central event in the pathogenesis of the inflammatory bowel diseases. We demonstrate that IFN-gamma has anti-inflammatory properties in the initiation phase of IL-23-mediated experimental colitis. IFN-gamma attenuates LPS-mediated IL-23 expression in murine macrophages. Mechanistically, IFN-gamma inhibits Il23a promoter activation through altering NF-kappaB binding and histone modification. Moreover, intestinal inflammation is inhibited by IFN-gamma signaling through attenuation of Il23a gene expression. In germ-free wild-type mice colonized with enteric microbiota, inhibition of colonic Il23a temporally correlates with induction of IFN-gamma. IFN-gammaR1/IL-10 double-deficient mice demonstrate markedly increased colonic inflammation and IL23a expression compared with those of IL-10(-/-) mice. Colonic CD11b(+) cells are the primary source of IL-23 and a target for IFN-gamma. This study describes an important anti-inflammatory role for IFN-gamma through inhibition of IL-23. Converging genetic and functional findings suggest that IL-23 and IFN-gamma are important pathogenic molecules in human inflammatory bowel disease.
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Shehzad Z
SZ
Sheikh
Katsuyoshi
K
Matsuoka
Taku
T
Kobayashi
Fengling
F
Li
Tara
T
Rubinas
Scott E
SE
Plevy
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology*; D053760:Interleukin-23 Subunit p19 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000276:immunology
C508841:Il23a protein, mouse; D018836:Inflammation Mediators; D053760:Interleukin-23 Subunit p19; D008070:Lipopolysaccharides; D007371:Interferon-gamma