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Frontline: Interferon regulatory factor-1 as a protective gene in intestinal inflammation: role of TCR γ δ T cells and interleukin-18-binding protein

  1. Britta Siegmund1,4,
  2. Joseph A. Sennello1,
  3. Hans A. Lehr2,
  4. Giorgio Senaldi3,5,
  5. Charles A. Dinarello1,
  6. Giamila Fantuzzi1,*

Article first published online: 22 JUL 2004

DOI: 10.1002/eji.200425124

Issue

European Journal of Immunology

European Journal of Immunology

Volume 34, Issue 9, pages 2356–2364, September 2004

Additional Information

How to Cite

Siegmund, B., Sennello, J., Lehr, H., Senaldi, G., Dinarello, C. and Fantuzzi, G. (2004), Frontline: Interferon regulatory factor-1 as a protective gene in intestinal inflammation: role of TCR γ δ T cells and interleukin-18-binding protein. European Journal of Immunology, 34: 2356–2364. doi: 10.1002/eji.200425124

Author Information

  1. 1

    Department of Medicine, University of Colorado Health Sciences Center, Denver, USA

  2. 2

    Institute of Pathology, University of Mainz, Mainz, Germany

  3. 3

    Amgen Inc., Thousand Oaks, USA

  4. 4

    Present address: Charité Universitaetsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik I, Berlin, Germany

  5. 5

    Present address: Abgenix, Inc., Fremont, CA, USA.

*University of Colorado, Department of Medicine, Box B168, 4200 East Ninth Avenue, Denver, CO 80262, USA, Fax: +1-303-315-8054

Publication History

  1. Issue published online: 5 AUG 2004
  2. Article first published online: 22 JUL 2004
  3. Manuscript Accepted: 26 APR 2004
  4. Manuscript Received: 18 MAR 2004

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Keywords:

  • IRF-1;
  • Intestinal inflammation;
  • γ δ T cells;
  • IL-18BP

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-γ 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-α, IL-1β, IL-15, and IL-18 were not significantly changed. Intestinal inflammation was not altered in IFN-γ KO mice or in WT mice given neutralizing anti-IFN-γ antibodies, but was increased in mice lacking TCR γ δ 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 γ δ cells appear to be critical factors inthe anti-inflammatory effects of IRF-1.

See accompanying article http://dx.doi.org/10.1002/eji.200425351

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