title: Characterization of an interferon-stimulated response element (ISRE) in the Il23a promoter.
abstract: We have demonstrated previously that IFN-γ plays a protective role in the initiation of chronic intestinal inflammation through attenuation of Toll-like receptor-mediated IL-23 induction in macrophages. Here, an interferon-stimulated response element (ISRE) is identified in a region of conserved nucleotide sequences in the Il23a promoter. This ISRE mediated, in part, Il23a promoter induction by LPS and inhibition of LPS-induced activity by IFN-γ. LPS and IFN-γ recruit interferon regulatory factors (IRFs) to the Il23a ISRE in murine bone marrow-derived macrophages (BMMs). Functionally, IRF-1 is a negative regulator of Il23a in LPS-stimulated BMMs. IRF-1(-/-) BMMs demonstrated enhanced LPS-induced Il23a expression compared with WT BMMs. Moreover, IRF-1 deficiency resulted in prolonged occupancy of RelA on the Il23a promoter. Consequently, IRF-1(-/-) mice were more susceptible to colonic injury by trinitrobenzenesulfonic acid, and IL-10/IRF-1 double-deficient (IL-10/IRF-1(-/-)) mice demonstrated more severe colonic inflammation compared with IL-10(-/-) mice. The severity of colitis in both models correlated with increased colonic IL-23. CD11b(+) lamina propria mononuclear cells, comprising predominantly macrophages, were identified as the major source of IL-23 in colitis-prone mice. Basal and heat-killed Escherichia coli-stimulated levels of Il23a were increased in IL-10/IRF-1(-/-) compared with WT and IL-10(-/-) colonic CD11b(+) lamina propria mononuclear cells. In conclusion, these experiments characterize IRF-ISRE interactions on the Il23a promoter, which have in vivo relevance as a homeostatic checkpoint in chronic intestinal inflammation.
authors.affiliation: Department of Medicine and Microbiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Shehzad Z
authors.initials: SZ
authors.lastname: Sheikh
authors.forename: Taku
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Onyiah
authors.forename: Scott E
authors.initials: SE
authors.lastname: Plevy
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics* / Q000276:immunology*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D053760:Interleukin-23 Subunit p19 / Q000235:genetics* / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D020218:Response Elements / Q000235:genetics* / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology / Q000378:metabolism
chemical_list: C508841:Il23a protein, mouse; D050856:Interferon Regulatory Factor-1; D053760:Interleukin-23 Subunit p19; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D016753:Interleukin-10; D007371:Interferon-gamma