Frontline: interferon regulatory factor-1 as a protective gene in intestinal inflammation: role of TCR gamma delta T cells and interleukin-18-binding protein

Abstract

The transcription factor IFN regulatory factor-1 (IRF-1) regulates production and activity of many inflammatory mediators and cells. Here, we investigated the role of IRF-1 in intestinal inflammation using clinical and histologic scores; inflammatory mediators were also measured in colonic tissue. Dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) was administered to wild-type (WT) or IRF-1 knockout (KO) mice. DSS or TNBS led to a dramatic increase in lethality and colitis severity in IRF-1 KO compared with WT mice. Reduced levels of IFN-gamma and IL-18-binding protein (IL-18BP) were observed in the colon of IRF-1 KO mice, whereas levels of inducible nitric oxide synthase, cyclooxygenase-2, phosphorylated STAT-3, chemokines, TNF-alpha, IL-1beta, IL-15, and IL-18 were not significantly changed. Intestinal inflammation was not altered in IFN-gamma KO mice or in WT mice given neutralizing anti-IFN-gamma antibodies, but was increased in mice lacking TCR gamma delta lymphocytes, a population significantly decreased in the intestine of IRF-1-deficient mice. Administration of IL-18BP reversed the increased susceptibility of IRF-1 KO mice to DSS. These results suggest a protective role for IRF-1 in intestinal inflammation, with a possible anti-inflammatory and/or restorative role. IL-18BP and TCR gamma delta cells appear to be critical factors in the anti-inflammatory effects of IRF-1.