| First Author | Huys L | Year | 2009 |
| Journal | J Exp Med | Volume | 206 |
| Issue | 9 | Pages | 1873-82 |
| PubMed ID | 19687227 | Mgi Jnum | J:152160 |
| Mgi Id | MGI:4356368 | Doi | 10.1084/jem.20090213 |
| Citation | Huys L, et al. (2009) Type I interferon drives tumor necrosis factor-induced lethal shock. J Exp Med 206(9):1873-82 |
| abstractText | 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-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. |
