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. (3rd March 2016)

• Record Type: Journal Article
• Authors: Yamaguchi, Rui; Yamamoto, Takatoshi; Sakamoto, Arisa; Ishimaru, Yasuji; Narahara, Shinji; Sugiuchi, Hiroyuki; Yamaguchi, Yasuo
• Is Part Of: Cell biology international. Volume 40:Number 6(2016)
• Page Start: 629
• Page End: 641
• Publication Date: 2016-03-03
• Subjects: granulocyte‐macrophage colony‐stimulating factor -- human neutrophil elastase -- interferon regulatory factor 5 -- interleukin‐12 -- macrophage; Cytology -- Periodicals; Cells -- Periodicals; 571.605
• DOI: 10.1002/cbin.10589
• Languages: English
• ISSNs: 1065-6995

Abstract

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.