S100A8 and S100A9—oxidant scavengers in inflammation |
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| Institution: | 1. Food Science & Technology Programme, Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Republic of Singapore;2. National University of Singapore (Suzhou) Research Institute, 377 Lin Quan Street, Suzhou Industrial Park, Jiangsu 215123, China;1. Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany;2. Institute of Pathology University Hospital RWTH Aachen, Germany;3. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany;4. Leukocyte Adhesion Laboratory, London Research Institute Cancer Research UK, London, UK;5. Department of Hepatology, Medical School Hannover, Hannover, Germany;6. Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany;7. Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany |
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| Abstract: | S100A8 and S100A9 are generally considered proinflammatory. Hypohalous acids generated by activated phagocytes promote novel modifications in murine S100A8 but modifications to human S100A8 are undefined and there is no evidence that these proteins scavenge oxidants in human disease. Recombinant S100A8 was exquisitely sensitive to equimolar ratios of HOCl, which generated sulfinic and sulfonic acid intermediates and novel oxathiazolidine oxide/dioxide forms (mass additions, m/z +30 and +46) on the single Cys42 residue. Met78(O) and Trp54(+16) were also present. HOBr generated sulfonic acid intermediates and oxidized Trp54(+16). Evidence for oxidation of the single Cys3 residue in recS100A9 HOCl was weak; Met63, Met81, Met83, and Met94 were converted to Met(O) in vitro. Oxidized S100A8 was prominent in lungs from patients with asthma and significantly elevated in sputum compared to controls, whereas S100A8 and S100A9 were not significantly increased. Oxidized monomeric S100A8 was the major component in asthmatic sputum, and modifications, including the oxathiazolidine adducts, were similar to those generated by HOCl in vitro. Oxidized Met63, Met81, and Met94 were variously present in S100A9 from asthmatic sputum. Results have broad implications for conditions under which hypohalous acid oxidants are generated by activated phagocytes. Identification in human disease of the novel S100A8 Cys derivatives typical of those generated in vitro strongly supports the notion that S100A8 contributes to antioxidant defense during oxidative stress. |
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