Frontline: interferon regulatory factor-1 as a protective gene in intestinal inflammation: role of TCR gamma delta T cells and interleukin-18-binding protein.
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.
Department of Medicine, University of Colorado Health Sciences Center, Denver, USA.
Britta
B
Siegmund
Joseph A
JA
Sennello
Hans A
HA
Lehr
Giorgio
G
Senaldi
Charles A
CA
Dinarello
Giamila
G
Fantuzzi
D000818:Animals; D003092:Colitis / Q000209:etiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D006023:Glycoproteins / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*
D004268:DNA-Binding Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; C118370:interleukin-18 binding protein; D007371:Interferon-gamma