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¹ Department for Molecular Biomedical Research, VIB, Ghent B9052, Belgium
² Department of Biomedical Molecular Biology, Ghent University, Ghent B9052, Belgium
³ Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig D-38124, Germany
⁴ Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent B-9000, Belgium

CORRESPONDENCE C. Libert: Claude.Libert{at}UGent.be

Tumor necrosis factor (TNF) is reputed to have very powerful antitumor effects, but it is also a strong proinflammatory cytokine. Injection of TNF in humans and mice leads to a systemic inflammatory response syndrome with major effects on liver and bowels. TNF is also a central mediator in several inflammatory diseases. We report that type I interferons (IFNs) are essential mediators of the lethal response to TNF. Mice deficient in the IFN- receptor 1 (IFNAR-1) or in IFN-β are remarkably resistant to TNF-induced hypothermia and death. After TNF injection, IFNAR-1^–/– mice produced less IL-6, had less bowel damage, and had less apoptosis of enterocytes and hepatocytes compared with wild-type (WT) mice. Extensive gene expression analysis in livers of WT and IFNAR-1^–/– mice revealed a large deficiency in the response to TNF in the knockout mice, especially of IFN-stimulated response element–dependent genes, many of which encode chemokines. In livers of IFNAR-1^–/– mice, fewer infiltrating white blood cells (WBCs) were detected by immunohistochemistry. Deficiency of type I IFN signaling provided sufficient protection for potentially safer therapeutic use of TNF in tumor-bearing mice. Our data illustrate that type I IFNs act as essential mediators in TNF-induced lethal inflammatory shock, possibly by enhancing cell death and inducing chemokines and WBC infiltration in tissues.

Abbreviations used: IFNAR-1, IFN- receptor 1; IHC, immunohistochemistry; iNOS, inducible nitric oxide synthase; ISRE, IFN-stimulated response element; SIRS, systemic inflammatory response syndrome; TSI, tumor size index; WBC, white blood cell.

© 2009 Huys et al.
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