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* Centre for Infection and Inflammation Research,
Bioanalytical Mass Spectrometry Facility,
Department of Physiology and Pharmacology, School of Medical Sciences, and
Centre for Vascular Research, University of New South Wales, Sydney, Australia; and
¶ Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia
S100A8 and S100A9, highly expressed by neutrophils, activated macrophages, and microvascular endothelial cells, are secreted during inflammatory processes. Our earlier studies showed S100A8 to be an avid scavenger of oxidants, and, together with its dependence on IL-10 for expression in macrophages, we postulated that this protein has a protective role. S-nitrosylation is an important posttranslational modification that regulates NO transport, cell signaling, and homeostasis. Relatively few proteins are targets of S-nitrosylation. To date, no inflammation-associated proteins with NO-shuttling capacity have been identified. We used HPLC and mass spectrometry to show that S100A8 and S100A9 were readily S-nitrosylated by NO donors. S-nitrosylated S100A8 (S100A8-SNO) was the preferred nitrosylated product. No S-nitrosylation occurred when the single Cys residue in S100A8 was mutated to Ala. S100A8-SNO in human neutrophils treated with NO donors was confirmed by the biotin switch assay. The stable adduct transnitrosylated hemoglobin, indicating a role in NO transport. S100A8-SNO suppressed mast cell activation by compound 48/80; intravital microscopy was used to demonstrate suppression of leukocyte adhesion and extravasation triggered by compound 48/80 in the rat mesenteric microcirculation. Although S100A8 is induced in macrophages by LPS or IFN-
, the combination, which activates inducible NO synthase, did not induce S100A8. Thus, the antimicrobial functions of NO generated under these circumstances would not be compromised by S100A8. Our results suggest that S100A8-SNO may regulate leukocyte-endothelial cell interactions in the microcirculation, and suppression of mast cell-mediated inflammation represents an additional anti-inflammatory property for S100A8.
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1 This work was supported by grants from the National Health and Medical Research Council of Australia.
2 S.Y.L. and M.R. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Carolyn L. Geczy, Centre for Infection and Inflammation Research, University of New South Wales, Sydney, NSW 2052, Australia. E-mail address: c.geczy{at}unsw.edu.au
4 Abbreviations used in this paper: iNOS, inducible NO synthase; β-hex, β-hexosaminidase; CMP48/80, compound 48/80; DEANO, diethylamine NONOate; EC, endothelial cell; GSH, glutathione; GSNO, S-nitrosoglutathione; HOCl, hypochlorite; HPRT, hypoxanthine-guanine phosphoribosyltransferase; hS100A8, human S100A8; MC, mast cell; MEC, microvascular endothelial cell; mS100A8, murine S100A8; OxyHb, oxygenated hemoglobin; RT, room temperature; S100A8-SNO, S-nitrosylated S100A8; SNAP, S-nitroso-N-acetylpenicillamine; SNO, S-nitrosothiol; TFA, trifluoroacetic acid; RP, reverse phase; ESI, electrospray ionization.
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