title: Cobalt Protoporphyrin Upregulates Cyclooxygenase-2 Expression Through a Heme Oxygenase-Independent Mechanism.
abstract: Cobalt protoporphyrin (CoPP) is a potent HO-1 inducer and generally known to be an antioxidant in various cell types. Little is known about the CoPP-induced cyclooxygenase-2 (COX-2) expression and its downstream signaling in microglial cells. In current study, CoPP caused concentration- and time-dependent increases in COX-2 expression in microglial cells. Furthermore, activation of apoptosis signal-regulating kinase (ASK) 1/MAP kinase involved in CoPP-induced COX-2 expression in microglia. CoPP also induced P2X7 receptor activation, and treatment of P2X7 inhibitors effectively reduced CoPP-induced COX-2 expression. Protein inhibitor of activated STAT (PIAS) 1 is reported to be involved in modulating anti-inflammatory response through negative regulation of transcription factors. Interestingly, treatment with CoPP markedly induced PIAS1 degradation which is regulated by PI3K, Akt, and glycogen synthase kinase 3α/β (GSK3α/β) signaling pathways. These results suggest that CoPP induces COX-2 expression through activating P2X7 receptors and ASK1/MAP kinases as well as PIAS1 degradation signaling pathways. Our study provides a new insight into the regulatory effect of CoPP on neuroinflammation in microglial cells.
authors.affiliation: Graduate Institute of Neural and Cognitive Sciences, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan.
authors.forename: Hsiao-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Neural and Cognitive Sciences, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan.|Department of Neurology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chon-Haw
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chingju
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Cell and Tissue Engineering, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Wei-Lan
authors.initials: WL
authors.lastname: Yeh
authors.affiliation: Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Cheng-Fang
authors.initials: CF
authors.lastname: Tsai
authors.affiliation: Department of Bioinformatics, Asia University, Taichung, Taiwan.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Ling-Hsuan
authors.initials: LH
authors.lastname: Wu
authors.affiliation: Graduate Institute of Neural and Cognitive Sciences, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan. dahyuu@mail.cmu.edu.tw.|Department of Photonics and Communication Engineering, Asia University, Taichung, Taiwan. dahyuu@mail.cmu.edu.tw.
authors.forename: Dah-Yuu
authors.initials: DY
authors.lastname: Lu
mesh_terms: D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D011524:Protoporphyrins; D058486:Receptors, Purinergic P2X7; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing); D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: COX-2; CoPP; HO-1; Microglia; Neuroinflammation