title: Tyrosine kinase 2 promotes sepsis-associated lethality by facilitating production of interleukin-27.
abstract: The aim of this study was to test the hypothesis that gene expression and release of IL-27 may be modulated by Tyk2. Macrophages derived from the peritoneum or bone marrow of C57BL/10SnJ (WT) mice produced abundant amounts of IL-27(p28) following TLR4 activation by LPS. In contrast, production of IL-27(p28), but not EBI3, was reduced by ∼50% in TLR4-activated macrophages derived from mice with genetic deficiency of Tyk2 compared with WT macrophages. Frequencies of IL-27(p28)+F4/80+CD11b+ cells were lower in TLR4-activated macrophages derived from Tyk2-/- mice. Mechanistically, Tyk2-/- resulted in disruption of a type I IFN-dependent mechanism for production of IL-27(p28), which was induced by type I IFNs, and release of IL-27 was defective in macrophages from IFN-β-/- and IFNAR1-/- mice. In contrast, Tyk2 was not required to mediate the effects of IL-27 on target gene expression in CD4(+) T cells. In vivo, we observed that Tyk2-/- mice have improved survival following endotoxic shock or polymicrobial sepsis induced by CLP. Plasma levels of IL-27(p28) during endotoxic shock or polymicrobial sepsis were markedly reduced in Tyk2-/- mice compared with WT mice. Disruption of IL-27 signaling using IL-27RA-/- mice was protective against sepsis-associated mortality. These data suggest that Tyk2 may mediate adverse outcomes of SIRS by promoting the production of IL-27. In conclusion, this report identifies Tyk2 as a prerequisite factor in the molecular networks that are involved in generation of IL-27.
authors.affiliation: Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany; markus.bosmann@unimedizin-mainz.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Bosmann
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Nadia
authors.initials: N
authors.lastname: Kichler
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Doris
authors.initials: D
authors.lastname: Rigler
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; and.
authors.forename: Jamison J
authors.initials: JJ
authors.lastname: Grailer
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; and.
authors.forename: Florence
authors.initials: F
authors.lastname: Pache
authors.affiliation: Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria;
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; and.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C508032:Ifnar1 protein, mouse; C486767:Il27 protein, mouse; D007378:Interleukins; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse
keywords: inflammation; interferon; lipopolysaccharide; macrophages; shock