title: A Toll-like receptor 2 ligand, Pam3CSK4, augments interferon-γ-induced nitric oxide production via a physical association between MyD88 and interferon-γ receptor in vascular endothelial cells.
abstract: The effect of Pam3CSK4, a Toll-like receptor 2 (TLR2) ligand, on interferon-γ (IFN-γ) -induced nitric oxide (NO) production in mouse vascular endothelial END-D cells was studied. Pre-treatment or post-treatment with Pam3CSK4 augmented IFN-γ-induced NO production via enhanced expression of an inducible NO synthase (iNOS) protein and mRNA. Pam3CSK4 augmented phosphorylation of Janus kinase 1 and 2, followed by enhanced phosphorylation of signal transducer and activator of transcription 1 (STAT1) at tyrosine 701. Subsequently, the enhanced STAT1 activation augmented IFN-γ-induced IFN-regulatory factor 1 expression leading to the iNOS expression. Pam3CSK4 also induced the activation of p38 and subsequent phosphorylation of STAT1 at serine 727. A pharmacological p38 inhibitor abolished the augmentation of IFN-γ-induced NO production by Pam3CSK4. Surprisingly, Pam3CSK4 enhanced a physical association of MyD88 and IFN-γ receptor. Together, these findings suggest that Pam3CSK4 up-regulates IFN-γ signalling in vascular endothelial cells via the physical association between MyD88 and IFN-γ receptor α, and p38-dependent serine 727 STAT1 phosphorylation.
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Bilegtsaikhan
authors.initials: B
authors.lastname: Tsolmongyn
authors.forename: Naoki
authors.initials: N
authors.lastname: Koide
authors.forename: Ulziisaikhan
authors.initials: U
authors.lastname: Jambalganiin
authors.forename: Erdenezaya
authors.initials: E
authors.lastname: Odkhuu
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Naiki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Komatsu
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Yoshida
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokochi
mesh_terms: D000818:Animals; D002460:Cell Line; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D055666:Lipopeptides / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D017471:Receptors, Interferon / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma; D055666:Lipopeptides; D048670:MAP Kinase Kinase 4; D053594:Myeloid Differentiation Factor 88; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D051195:Toll-Like Receptor 2; D048051:p38 Mitogen-Activated Protein Kinases; D000096743:Interferon gamma Receptor; C508075:Pam(3)CSK(4) peptide; C079868:gamma interferon activation factor
keywords: MyD88; Pam3CSK4; Toll-like receptor 2; interferon-γ receptor; vascular endothelial cells