title: Type I interferon drives tumor necrosis factor-induced lethal shock.
abstract: 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.
authors.affiliation: Department for Molecular Biomedical Research, VIB, Ghent B9052, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Huys
authors.forename: Filip
authors.initials: F
authors.lastname: Van Hauwermeiren
authors.forename: Lien
authors.initials: L
authors.lastname: Dejager
authors.forename: Eline
authors.initials: E
authors.lastname: Dejonckheere
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.forename: Georges
authors.initials: G
authors.lastname: Leclercq
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D007035:Hypothermia / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007370:Interferon Type I / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta
references.citation: Int J Cancer. 1986 Nov 15;38(5):763-9
references.pmid: 3095251
references.citation: Am J Physiol Gastrointest Liver Physiol. 2003 Apr;284(4):G695-702
references.pmid: 12529262
references.citation: Trends Immunol. 2005 Oct;26(10):506-9
references.pmid: 16087400
references.citation: Eur Cytokine Netw. 1996 Apr-Jun;7(2):93-124
references.pmid: 8688493
references.citation: Science. 1986 Oct 24;234(4775):470-4
references.pmid: 3764421
references.citation: Nat Immunol. 2003 May;4(5):471-7
references.pmid: 12679810
references.citation: Science. 1994 Jun 24;264(5167):1918-21
references.pmid: 8009221
references.citation: Annu Rev Immunol. 1994;12:85-116
references.pmid: 8011300
references.citation: Infect Immun. 2007 Jan;75(1):22-9
references.pmid: 17000722
references.citation: Nat Immunol. 2006 Jan;7(1):33-9
references.pmid: 16311601
references.citation: Mod Pathol. 1991 Nov;4(6):733-41
references.pmid: 1724087
references.citation: Eur J Immunol. 1994 Sep;24(9):2237-42
references.pmid: 7522168
references.citation: Am J Physiol Cell Physiol. 2008 Jan;294(1):C153-60
references.pmid: 18032529
references.citation: J Cell Mol Med. 2004 Oct-Dec;8(4):445-54
references.pmid: 15601573
references.citation: Immunol Ser. 1992;56:409-30
references.pmid: 1550870
references.citation: Ann Oncol. 2004;15 Suppl 4:iv107-12
references.pmid: 15477292
references.citation: Immunol Rev. 1999 Jun;169:175-94
references.pmid: 10450517
references.citation: J Interferon Cytokine Res. 2006 Jun;26(6):373-9
references.pmid: 16734557
references.citation: Curr Med Chem. 2007;14(12):1279-89
references.pmid: 17504213
references.citation: Cell Prolif. 2008 Dec;41(6):960-979
references.pmid: 19040572
references.citation: Nat Immunol. 2008 Apr;9(4):378-87
references.pmid: 18345002
references.citation: Immunity. 2000 Aug;13(2):223-31
references.pmid: 10981965
references.citation: J Immunol. 2007 Aug 1;179(3):1595-604
references.pmid: 17641026
references.citation: Eur J Immunol. 1998 Nov;28(11):3499-505
references.pmid: 9842892
references.citation: J Immunol. 2008 Aug 1;181(3):2092-102
references.pmid: 18641348
references.citation: J Biol Chem. 2004 Dec 31;279(53):55609-17
references.pmid: 15489234
references.citation: Nat Med. 2001 Nov;7(11):1202-8
references.pmid: 11689884
references.citation: Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W128-32
references.pmid: 18453628
references.citation: Curr Top Microbiol Immunol. 2007;316:71-95
references.pmid: 17969444
references.citation: J Immunol. 1994 May 15;152(10):5041-9
references.pmid: 8176222
references.citation: Proc Natl Acad Sci U S A. 1986 Dec;83(24):9679-83
references.pmid: 2948184
references.citation: J Exp Med. 2008 Aug 4;205(8):1755-61
references.pmid: 18663129
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15623-8
references.pmid: 9861020