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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cell Line
-
Cells, Cultured
-
Colony-Forming Units Assay
-
Cytokines / biosynthesis*
-
Cytokines / deficiency
-
Cytokines / genetics
-
DNA-Binding Proteins / antagonists & inhibitors
-
DNA-Binding Proteins / deficiency
-
DNA-Binding Proteins / metabolism
-
Down-Regulation / genetics
-
Down-Regulation / immunology
-
Embryo, Mammalian
-
Fibroblasts
-
Genetic Predisposition to Disease
-
Granulocyte Colony-Stimulating Factor / pharmacology
-
Growth Inhibitors*
-
Humans
-
Interferon Type I / metabolism
-
Interferon Type I / pharmacology
-
Interferon gamma Receptor
-
Interferon-gamma / metabolism
-
Interleukin-10 / pharmacology
-
Interleukin-12 / pharmacology
-
Interleukin-3 / pharmacology
-
Interleukin-6 / pharmacology
-
Leukemia Inhibitory Factor
-
Leukemia Inhibitory Factor Receptor alpha Subunit
-
Lipopolysaccharides / pharmacology
-
Lymphocyte Activation / genetics
-
Lymphocytic Choriomeningitis / genetics
-
Lymphocytic Choriomeningitis / immunology
-
Lymphokines*
-
Macrophages / immunology
-
Macrophages / metabolism
-
Membrane Proteins
-
Mice
-
Mice, Inbred Strains
-
Myeloid Progenitor Cells / cytology
-
Nitric Oxide / biosynthesis
-
Protein-Tyrosine Kinases / deficiency*
-
Protein-Tyrosine Kinases / genetics*
-
Protein-Tyrosine Kinases / physiology
-
Proteins / genetics*
-
Proteins / physiology
-
Receptor, Interferon alpha-beta
-
Receptors, Cytokine / physiology
-
Receptors, Interferon / antagonists & inhibitors
-
Receptors, Interferon / physiology
-
Receptors, OSM-LIF
-
Rhabdoviridae Infections / genetics
-
Rhabdoviridae Infections / immunology
-
STAT3 Transcription Factor
-
Signal Transduction / genetics
-
Signal Transduction / immunology
-
Spleen / cytology
-
Spleen / enzymology
-
Spleen / immunology
-
TYK2 Kinase
-
Thrombopoietin / pharmacology
-
Trans-Activators / antagonists & inhibitors
-
Trans-Activators / deficiency
-
Trans-Activators / metabolism
-
Vaccinia / genetics
-
Vaccinia / immunology
-
Vesicular stomatitis Indiana virus / immunology
Substances
-
Cytokines
-
DNA-Binding Proteins
-
Growth Inhibitors
-
Interferon Type I
-
Interleukin-3
-
Interleukin-6
-
LIF protein, human
-
LIFR protein, human
-
Leukemia Inhibitory Factor
-
Leukemia Inhibitory Factor Receptor alpha Subunit
-
Lif protein, mouse
-
Lifr protein, mouse
-
Lipopolysaccharides
-
Lymphokines
-
Membrane Proteins
-
Proteins
-
Receptors, Cytokine
-
Receptors, Interferon
-
Receptors, OSM-LIF
-
STAT3 Transcription Factor
-
STAT3 protein, human
-
Stat3 protein, mouse
-
Trans-Activators
-
Interleukin-10
-
Granulocyte Colony-Stimulating Factor
-
Receptor, Interferon alpha-beta
-
Interleukin-12
-
Nitric Oxide
-
Interferon-gamma
-
Thrombopoietin
-
Protein-Tyrosine Kinases
-
TYK2 Kinase
-
TYK2 protein, human
-
Tyk2 protein, mouse