title: Organ-specific and differential requirement of TYK2 and IFNAR1 for LPS-induced iNOS expression in vivo.
abstract: Lipopolysaccharide (LPS) is an integral structural component of the outer membrane of Gram-negative bacteria and the principal active agent in the pathogenesis of endotoxin shock. LPS is a potent inducer of a variety of cytokines and inflammatory agents that lead to a profound alteration of gene expression patterns in cells and organs. The gene coding for the inducible nitric oxide synthase (iNOS) is highly responsive to LPS in vitro and in vivo and accounts for the production of nitric oxide (NO). The Janus kinase (JAK) family member tyrosine kinase 2 (TYK2) is a constituent of the interferon (IFN) type I response pathway and an important effector in the progression of endotoxin shock. Macrophages deficient for IFNalphabeta receptor chain 1 (IFNAR1) or TYK2 were shown to have an impaired LPS-induced iNOS expression. Here we determined the contribution of IFNAR1 and TYK2 to iNOS expression in vivo in a lethal LPS challenge model. TYK2 and IFNAR1 were found to be crucial for the LPS-induced iNOS mRNA and protein expression in spleen and lung that could be attributed to the Mac3-positive population. In liver LPS-induced iNOS mRNA expression was only partially impaired in TYK2-deficient mice and was unimpaired in IFNAR1-deficient mice, indicating organ specificity. TYK2(-/-) and IFNAR1(-/-) mice also differ with respect to IFNgamma production upon LPS challenge in that TYK2(-/-) mice show a defect while IFNAR1(-/-) mice do not. Our data suggest that iNOS is induced through IFNAR1 and TYK2 in Mac3-positive cells which are the main source of iNOS in spleen and lung. The LPS-induced iNOS expression in liver is independent of IFNAR1 and partially dependent on TYK2, which is most likely due to the lack of IFNgamma production in the absence of TYK2.
authors: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, A-1210, Vienna, Austria.
authors: Ronald
authors: R
authors: Painz
authors: Ingrid
authors: I
authors: Walter
authors: Thomas
authors: T
authors: Kolbe
authors: Doris
authors: D
authors: Rigler
authors: Claus
authors: C
authors: Vogl
authors: Ralf
authors: R
authors: Steinborn
authors: Thomas
authors: T
authors: Rülicke
authors: Magdalena
authors: M
authors: Helmreich
authors: Marina
authors: M
authors: Karaghiosoff
authors: Mathias
authors: M
authors: Müller
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis; D007370:Interferon Type I / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D009928:Organ Specificity; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D053634:TYK2 Kinase / Q000378:metabolism*
chemical_list: D000943:Antigens, Differentiation; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D008070:Lipopolysaccharides; C036763:monocyte-macrophage differentiation antigen; D053633:Receptor, Interferon alpha-beta; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D053634:TYK2 Kinase