Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a promoter

Shehzad Z. Sheikh, Taku Kobayashi, Katsuyoshi Matsuoka, Joseph C. Onyiah, Scott E. Plevy

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1174-1180
Number of pages7
JournalJournal of Biological Chemistry
Volume286
Issue number2
DOIs
Publication statusPublished - 2011 Jan 14

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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