title: Partial impairment of cytokine responses in Tyk2-deficient mice.
abstract: To assess the role of the Janus kinase (Jak) family member Tyk2, we have generated Tyk2-/- mice. In contrast to other Jaks, where inactivation leads to a complete loss of the respective cytokine receptor signal, Tyk2-/- mice display reduced responses to IFNalpha/beta and IL-12 and a selective deficiency in Stat3 activation in these pathways. Unexpectedly, IFNgamma signaling is also impaired in Tyk2-/- mice. Tyk2-/- macrophages fail to produce nitric oxide upon lipopolysaccharide induction. Tyk2-/- mice are unable to clear vaccinia virus and show a reduced T cell response after LCMV challenge. These data imply a selective contribution of Tyk2 to the signals triggered by various biological stimuli and cytokine receptors.
authors.affiliation: Institute of Animal Breeding and Genetics, Veterinary University of Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Karaghiosoff
authors.forename: H
authors.initials: H
authors.lastname: Neubauer
authors.forename: C
authors.initials: C
authors.lastname: Lassnig
authors.forename: P
authors.initials: P
authors.lastname: Kovarik
authors.forename: H
authors.initials: H
authors.lastname: Schindler
authors.forename: H
authors.initials: H
authors.lastname: Pircher
authors.forename: B
authors.initials: B
authors.lastname: McCoy
authors.forename: C
authors.initials: C
authors.lastname: Bogdan
authors.forename: T
authors.initials: T
authors.lastname: Decker
authors.forename: G
authors.initials: G
authors.lastname: Brem
authors.forename: K
authors.initials: K
authors.lastname: Pfeffer
authors.forename: M
authors.initials: M
authors.lastname: Müller
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004622:Embryo, Mammalian; D005347:Fibroblasts; D020022:Genetic Predisposition to Disease; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006131:Growth Inhibitors; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology; D008222:Lymphokines; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D023461:Myeloid Progenitor Cells / Q000166:cytology; D009569:Nitric Oxide / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D053633:Receptor, Interferon alpha-beta; D018121:Receptors, Cytokine / Q000502:physiology; D017471:Receptors, Interferon / Q000037:antagonists & inhibitors / Q000502:physiology; D053606:Receptors, OSM-LIF; D018353:Rhabdoviridae Infections / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D053634:TYK2 Kinase; D013926:Thrombopoietin / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D014615:Vaccinia / Q000235:genetics / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D016179:Granulocyte Colony-Stimulating Factor; D006131:Growth Inhibitors; D007370:Interferon Type I; D007371:Interferon-gamma; D016753:Interleukin-10; D018664:Interleukin-12; D007377:Interleukin-3; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008070:Lipopolysaccharides; D008222:Lymphokines; D008565:Membrane Proteins; D009569:Nitric Oxide; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D053633:Receptor, Interferon alpha-beta; D018121:Receptors, Cytokine; D017471:Receptors, Interferon; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; D053634:TYK2 Kinase; D013926:Thrombopoietin; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C507837:LIF protein, human; C507840:LIFR protein, human; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse