Health & Environmental Research Online (HERO)


Print Feedback Export to File
508220 
Journal Article 
Organ-specific and differential requirement of TYK2 and IFNAR1 for LPS-induced NOS expression in vivo 
Painz, R; Walter, I; Kolbe, T; Rigler, D; Vogl, C; Steinborn, R; Rulicke, T; Helmreich, M; Karaghiosoff, M; Muller, M 
2007 
Yes 
Immunobiology
ISSN: 0171-2985 
212 
9-10 
863-875 
English 
18086385 
WOS:000252620000017 
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 (NOS) 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 IFN alpha beta receptor chain 1 (IFNARI) or TYK2 were shown to have an impaired LPS-induced NOS expression. Here we determined the contribution of IFNARI and TYK2 to NOS expression in vivo in a lethal LPS challenge model. TYK2 and IFNARI 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 NOS 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 IFN production upon LPS challenge in that TYK2(-/-) mice show a defect while IFNAR1(-/-) mice do not. Our data suggest that NOS is induced through IFNARI and TYK2 in Mac3-positive cells which are the main source of NOS in spleen and lung. The LPS-induced NOS expression in liver is independent of IFNAR1 and partially dependent on TYK2, which is most likely due to the lack of IFN production in the absence of TYK2. (c) 2007 Elsevier GmbH. All rights reserved. 
endotoxin shock; interferon alpha/beta receptor 1; JAK-STAT signaling; Janus kinase; type I interferon; nitric-oxide synthase; tumor-necrosis-factor; mouse; peritoneal-macrophages; interferon-gamma; monoclonal-antibodies; bacterial-infection; gene-expression; endotoxic-shock; factor-alpha; tnf-alpha