A pivotal role for NF-κB in the macrophage inflammatory response to the myeloperoxidase oxidant hypothiocyanous acid.
Atherosclerosis is characterised by the infiltration of macrophages at sites of inflammation within the vessel wall and the release of myeloperoxidase (MPO), which forms hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). HOCl is a damaging oxidant implicated in the development of atherosclerosis. Preferential formation of HOSCN occurs under conditions where thiocyanate ions are elevated, as is the case in smokers. HOSCN reacts selectively with thiols, which can result in more enzyme inactivation and damage than HOCl at susceptible sites, which may contribute to atherosclerosis in smokers. In this study, we show that exposure of macrophages to HOSCN results in a time- and dose-dependent increase in the mRNA expression and release of pro-inflammatory cytokines and chemokines, including monocyte chemotactic protein 1, tumour necrosis factor alpha, and interleukins 6, 8 and 1β. At high oxidant concentrations (>200 μM), a significant loss of cellular thiols and increased cell death is observed. HOSCN-induced cytokine/chemokine expression and cell death were decreased on pharmacological inhibition of nuclear factor kappa B. These data highlight a pathway by which HOSCN could promote inflammation and the development of atherosclerosis, in the presence of supra-physiological levels of the precursor thiocyanate, which are achievable by cigarette smoking.
['Pan|Gary J|GJ|', 'Rayner|Benjamin S|BS|', 'Zhang|Yunjia|Y|', 'van Reyk|David M|DM|', 'Hawkins|Clare L|CL|']
D050197:Atherosclerosis D002454:Cell Differentiation D002460:Cell Line D002470:Cell Survival D018925:Chemokines D016207:Cytokines D006801:Humans D007249:Inflammation D018836:Inflammation Mediators D008264:Macrophages D016328:NF-kappa B D009195:Peroxidase D012907:Smoking D013438:Sulfhydryl Compounds D013755:Tetradecanoylphorbol Acetate D013861:Thiocyanates D015854:Up-Regulation
Macrophage Myeloperoxidase Atherosclerosis Inflammation Cytokine Oxidative stress