title: Salubrinal acts as a Dusp2 inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis.
abstract: Dual-specificity phosphatase 2 (Dusp2; also called phosphatase of activated cells 1, PAC1) is highly expressed in activated immune cells. We examined whether a potential inhibitor of Dusp2, salubrinal, prevents inflammatory cytokine expression in immune cells and arthritic responses in a mouse model of anti-collagen antibody-induced arthritis (CAIA). Salubrinal is a synthetic chemical that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). In this study, we examined the effects of salubrinal on expression of inflammation linked genes as well as a family of DUSP genes using genome-wide microarrays, qPCR, and RNA interference. We also evaluated the effects of salubrinal on arthritic responses in CAIA mice using clinical and histological scores. The results revealed that salubrinal decreased inflammatory gene expression in macrophages, T lymphocytes, and mast cells. Dusp2 was suppressed by salubrinal in LPS-activated macrophages as well as PMA/ionomycin-activated T lymphocytes and mast cells. Furthermore, a partial silencing of Dusp2 downregulated IL1β and Cox2, and the inflammatory signs of CAIA mice were significantly suppressed by salubrinal. Collectively, this study presents a novel therapeutic possibility of salubrinal for inflammatory arthritis such as RA through inhibition of Dusp2.
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA. Electronic address: hamak@dpc.agu.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Hamamura
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA; Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Mie 514, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA; Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Mie 514, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Takigawa
authors.affiliation: Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Mie 514, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sudo
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokota
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D002934:Cinnamates / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D054641:Dual Specificity Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D034622:RNA Interference; D013890:Thiourea / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D002934:Cinnamates; D016207:Cytokines; D053583:Interleukin-1beta; C496827:salubrinal; D054641:Dual Specificity Phosphatase 2; C517033:Dusp2 protein, mouse; D013890:Thiourea
keywords: CAIA; Dusp2 (PAC1); Inflammation; Microarray; Salubrinal