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dc.contributor.authorHuys, Liesbeth
dc.contributor.authorVan Hauwermeiren, Filip
dc.contributor.authorDejager, Lien
dc.contributor.authorDejonckheere, Eline
dc.contributor.authorLienenklaus, Stefan
dc.contributor.authorWeiss, Siegfried
dc.contributor.authorLeclercq, Georges
dc.contributor.authorLibert, Claude
dc.date.accessioned2009-12-02T15:31:30Z
dc.date.available2009-12-02T15:31:30Z
dc.date.issued2009-08-31
dc.identifier.citationType I interferon drives tumor necrosis factor-induced lethal shock. 2009, 206 (9):1873-82 J. Exp. Med.en
dc.identifier.issn1540-9538
dc.identifier.pmid19687227
dc.identifier.doi10.1084/jem.20090213
dc.identifier.urihttp://hdl.handle.net/10033/87237
dc.description.abstractTumor 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-alpha receptor 1 (IFNAR-1) or in IFN-beta 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.
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshGene Expression Profilingen
dc.subject.meshHypothermiaen
dc.subject.meshImmunohistochemistryen
dc.subject.meshIn Situ Nick-End Labelingen
dc.subject.meshInterferon Type Ien
dc.subject.meshInterleukin-6en
dc.subject.meshLiveren
dc.subject.meshMiceen
dc.subject.meshMice, Knockouten
dc.subject.meshReceptor, Interferon alpha-betaen
dc.subject.meshSignal Transductionen
dc.subject.meshSystemic Inflammatory Response Syndromeen
dc.subject.meshTumor Necrosis Factor-alphaen
dc.titleType I interferon drives tumor necrosis factor-induced lethal shock.en
dc.typeArticleen
dc.contributor.departmentDepartment for Molecular Biomedical Research, VIB, Ghent B9052, Belgium.en
dc.identifier.journalThe Journal of experimental medicineen
refterms.dateFOA2018-06-12T22:08:14Z
html.description.abstractTumor 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-alpha receptor 1 (IFNAR-1) or in IFN-beta 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.


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