title: A protease-activated receptor 2 agonist (AC-264613) suppresses interferon regulatory factor 5 and decreases interleukin-12p40 production by lipopolysaccharide-stimulated macrophages: Role of p53.
abstract: The transcription factor interferon regulatory factor 5 (IRF5) has a key role in the production of interleukin (IL)-12 by macrophages. IRF5 is also a central mediator of toll-like receptor signaling and is a direct target of p53. Activation of protease-activated receptor 2 (PAR-2) upregulates p53 and suppresses apoptosis. This study investigated the influence of human neutrophil elastase (HNE) and PAR-2 agonists on expression of IRF5 and IL-12p40 by macrophages stimulated with lipopolysaccharide. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent macrophages showed upregulation of IRF5 expression, while HNE reduced expression of p53 and IRF5 in a concentration-dependent manner. HNE also caused a concentration-dependent decrease of IRF5 in macrophages transfected with small interfering RNA to silence p53, while silencing of β-arrestin 2 blunted the reduction of p53 or IRF5 by HNE. Incubation of macrophages with a PAR-2 agonist, AC-264613, caused a decrease of IRF5 expression and also significantly reduced p53 protein expression. HNE upregulated the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) and caused transactivation of TLR4, while AC-264613 did not promote TLR4 transactivation. In conclusion, the PAR-2 agonist AC-264613 attenuated IRF5-associated IL-12p40 production by macrophages.
authors.affiliation: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto, 861-5598, Japan.|Graduate School of Medical Science, Kumamoto University Medical School, Chuo-ku Honjo 1-1-1, Kumamoto, 860-8556, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto, 861-5598, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto, 861-5598, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto, 861-5598, Japan.
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Ishimaru
authors.affiliation: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto, 861-5598, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Narahara
authors.affiliation: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto, 861-5598, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugiuchi
authors.affiliation: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto, 861-5598, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yamaguchi
mesh_terms: D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis* / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000819:agonists* / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C487404:2-furoyl-LIGRLO-amide; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D009842:Oligopeptides; D034741:RNA, Small Interfering; D044464:Receptor, PAR-2; C495345:TLR4 protein, human; C495901:TP53 protein, human; D051197:Toll-Like Receptor 4; D016159:Tumor Suppressor Protein p53; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019272:Leukocyte Elastase
keywords: granulocyte-macrophage colony-stimulating factor; human neutrophil elastase; interferon regulatory factor 5; interleukin-12; macrophage