title: HO-1 induction by CO-RM2 attenuates TNF-α-induced cytosolic phospholipase A2 expression via inhibition of PKCα-dependent NADPH oxidase/ROS and NF-κB.
abstract: Rheumatoid arthritis (RA) is characterized by chronic inflammatory infiltration of the synovium and elevation of proinflammatory cytokines. Cytosolic phospholipase A2 (cPLA2) is involved in the development of inflammatory diseases. Heme oxygenase-1 (HO-1) has been shown to possess anti-inflammatory properties. The objective of the study was to investigate the detailed mechanisms of TNF-α-induced cPLA2 expression and to determine whether carbon monoxide releasing molecule-2 (CO-RM2) suppresses TNF-α-induced expression of NF-κB-related proinflammatory genes, including cPLA2, via HO-1 induction in RA synovial fibroblasts (RASFs). Here, we reported that TNF-α-induced cPLA2 expression was mediated through TNFR1/PKCα-dependent signaling pathways, including NADPH oxidase (NOX) activation/ROS production and NF-κB activation. CO-RM2 significantly suppressed TNF-α-induced cPLA2 expression by inhibiting the ROS generation and the phosphorylation of NF-κB p65 and IKK α/β, but not the phosphorylation of p38 MAPK and JNK1/2. These results were further confirmed by a ChIP assay to detect the NF-κB DNA-binding activity. Our results demonstrated that induction of HO-1 by CO-RM2 exerted anti-inflammatory and antioxidant effects which were required in concert to prevent the activation of NF-κB leading to induction of various inflammatory genes implicated in the pathogenesis of RA.
authors.affiliation: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan.
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Chi
authors.affiliation: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan.
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan ; Department of Anesthetics, Chang Gung Memorial Hospital at Linkou and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan.
authors.forename: I-Ta
authors.initials: IT
authors.lastname: Lee
authors.affiliation: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan.
authors.forename: Li-Der
authors.initials: LD
authors.lastname: Hsiao
authors.affiliation: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 333, Taiwan.
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D000818:Animals; D003600:Cytosol / Q000201:enzymology; D015232:Dinoprostone / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009942:Organometallic Compounds / Q000737:chemistry; D054467:Phospholipases A2 / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013583:Synovial Membrane / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C447082:tricarbonyldichlororuthenium (II) dimer; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019255:NADPH Oxidases; D051571:Protein Kinase C-alpha; D054467:Phospholipases A2; D015232:Dinoprostone