Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05109 (S100A8)
 1,212 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The myeloid cell-derived calcium-binding murine protein, S100A8, is secreted to act as a chemotactic factor at picomolar concentrations, stimulating recruitment of myeloid cells to inflammatory sites. S100A8 may be exposed to oxygen metabolites, particularly hypochlorite, the major oxidant generated by activated neutrophils at inflammatory sites. Here we show that hypochlorite oxidizes the single Cys residue (Cys41) of S100A8. Electrospray mass spectrometry and SDS-polyacrylamide gel electrophoresis analysis indicated that low concentrations of hypochlorite (40 microM) converted 70-80% of S100A8 to the disulfide-linked homodimer. The mass was 20,707 Da, 92 Da more than expected, indicating additional oxidation of susceptible amino acids (possibly methionine). Phorbol 12-myristate 13-acetate activation of differentiated HL-60 granulocytic cells generated an oxidative burst that was sufficient to efficiently oxidize exogenous S100A8 within 10 min, and results implicate involvement of the myeloperoxidase system. Moreover, disulfide-linked dimer was identified in lung lavage fluid of mice with endotoxin-induced pulmonary injury. S100A8 dimer was inactive in chemotaxis and failed to recruit leukocytes in vivo. Positive chemotactic activity of recombinant Ala41S100A8 indicated that Cys41 was not essential for function and suggested that covalent dimerization may structurally modify accessibility of the chemotactic hinge domain. Disulfide-dependent dimerization may be a physiologically significant regulatory mechanism controlling S100A8-provoked leukocyte recruitment.
 ...
PMID:Oxidation regulates the inflammatory properties of the murine S100 protein S100A8. 1008 90

The murine calcium binding protein S100A8 (A8) is a leukocyte chemoattractant, but high levels may be protective and scavenge hypochlorite. A8 is induced by LPS, IFN-gamma, and TNF in elicited macrophages. Th2 cytokines generally suppress proinflammatory gene expression, and IL-4 and IL-13 partially decreased A8 induction in macrophages and endothelial cells stimulated by LPS or IFN. In contrast, IL-10 synergized with LPS and IFN to increase mRNA levels > or =9-fold and secreted A8 levels approximately 4-fold. IL-10 decreased the optimal time of mRNA expression induced by LPS from 24 to 8 h. Blocking experiments indicated that endogenous IL-10 contributes to gene induction by LPS. Cooperation between IL-10 and LPS was not due to altered mRNA stability but was dependent on de novo protein synthesis. Transfection analysis with A8 luciferase constructs confirmed that synergy was due to increased transcription. The region of the promoter involved was localized to a 178-bp fragment flanking the transcription start site of the gene. This region was also responsible for the suppressive effects of IL-4 and IL-13. Forskolin, CTP-cAMP, and PGE(2) also enhanced LPS- and IFN-induced A8 mRNA, whereas indomethacin significantly reduced synergy between IL-10 and LPS. Mitogen-activated protein kinase/cyclooxygenase 2/cAMP pathways involving CCAAT-enhancing binding protein, located within the active promoter, may mediate A8 gene up-regulation in a manner mechanistically distinct to genes regulated by IL-10 via the STAT pathway. A8 exhibits pleiotropic effects, and the high levels secreted as a result of IL-10 synergy may regulate untoward inflammatory damage by virtue of its an antioxidant capacity.
 ...
PMID:Il-10 up-regulates macrophage expression of the S100 protein S100A8. 1134 60

Hypochlorite is a major oxidant generated when neutrophils and macrophages are activated at inflammatory sites, such as in atherosclerotic lesions. Murine S100A8 (A8) is a major cytoplasmic protein in neutrophils and is secreted by macrophages in response to inflammatory stimuli. After incubation with reagent HOCl for 10 min, approximately 85% of A8 was converted to 4 oxidation products, with electrospay ionization mass spectrometry masses of m/z 10354, 10388, 10354 +/- 1, and 20707 +/- 3. All were resistant to reduction by dithiothreitol. Initial formation of a reactive Cys sulfenic acid intermediate was demonstrated by the rapid conjugation of 5,5-dimethyl-1,3-cyclohexanedione (dimedone) to HOCl-treated A8 to form stable adducts. Matrix-assisted laser desorption-reflectron time of flight peptide mass fingerprinting of isolated oxidation products confirmed the mass additions observed in the full-length proteins. Both Met(36/73) were converted to Met(36/73) sulfoxides. An additional product with an unusual mass addition of m/z 14 (+/-0.2) was identified and corresponded to the addition of oxygen to Cys(41), conjugation to various epsilon-amines of Lys(6), Lys(34/35), or Lys(87) with loss of dihydrogen and formation of stable intra- or inter-molecular sulfinamide cross-links. Specific fragmentations identified in matrix-assisted laser desorption-post source decay spectra and low energy collisional-induced dissociation tandem mass spectroscopy spectra of sulfinamide-containing digest peptides confirmed Lys(34/35) to Cys(41) sulfinamide bonds. HOCl oxidation of mutants lacking Cys(41) (Ala(41)S100A8) or specific Lys residues (e.g. Lys(34/35), Ala(34/35)S100A8) did not form sulfinamide cross-links. HOCl generated by myeloperoxidase and H(2)O(2) and by phorbol 12-myristate 13-acetate-activated neutrophils also formed these products(.) In contrast to the disulfide-linked dimer, oxidized monomer retained normal chemotactic activity for neutrophils. Sulfinamide bond formation represents a novel oxidative cross-linking process between thiols and amines and may be a general consequence of HOCl protein oxidation in inflammation not identified previously. Similar modifications in other proteins could potentially regulate normal and pathological processes during aging, atherogenesis, fibrosis, and neurogenerative diseases.
 ...
PMID:Novel intra- and inter-molecular sulfinamide bonds in S100A8 produced by hypochlorite oxidation. 1144 63

Atherogenesis is a complex process involving inflammation. S100A8 and S100A9, the Ca2+-binding neutrophil cytosolic proteins, are associated with innate immunity and regulate processes leading to leukocyte adhesion and transmigration. In neutrophils and monocytes the S100A8-S100A9 complex regulates phosphorylation, NADPH-oxidase activity, and fatty acid transport. The proteins have anti-microbial properties, and S100A8 may play a role in oxidant defense in inflammation. Murine S100A8 is regulated by inflammatory mediators and recruits macrophages with a proatherogenic phenotype. S100A9 but not S100A8 was found in macrophages in ApoE-/- murine atherosclerotic lesions, whereas both proteins are expressed in human giant cell arteritis. Here we demonstrate S100A8 and S100A9 protein and mRNA in macrophages, foam cells, and neovessels in human atheroma. Monomeric and complexed forms were detected in plaque extracts. S100A9 was strongly expressed in calcifying areas and the surrounding extracellular matrix. Vascular matrix vesicles contain high levels of Ca2+-binding proteins and phospholipids that regulate calcification. Matrix vesicles characterized by electron microscopy, x-ray microanalysis, nucleoside triphosphate pyrophosphohydrolase assay and cholesterol/phospholipid analysis contained predominantly S100A9. We propose that S100A9 associated with lipid structures in matrix vesicles may influence phospholipid-Ca2+ binding properties to promote dystrophic calcification. S100A8 and S100A9 were more sensitive to hypochlorite oxidation than albumin or low density lipoprotein and immunoaffinity confirmed S100A8-S100A9 complexes; some were resistant to reduction, suggesting that hypochlorite may contribute to protein cross-linking. S100A8 and S100A9 in atherosclerotic plaque and calcifying matrix vesicles may significantly influence redox- and Ca2+-dependent processes during atherogenesis and its chronic complications, particularly dystrophic calcification.
 ...
PMID:S100A8 and S100A9 in human arterial wall. Implications for atherogenesis. 1621 73

This review focuses on new aspects of extracellular roles of the calgranulins. S100A8, S100A9 and S100A12 are constitutively expressed in neutrophils and induced in several cell types. The S100A8 and S100A9 genes are regulated by pro- and anti-inflammatory mediators and their functions may depend on cell type, mediators within a particular inflammatory milieu, receptors involved in their recognition and their post-translational modification. The S100A8 gene induction in macrophages is dependent on IL-10 and potentiated by immunosuppressive agents. S100A8 and S100A9 are oxidized by peroxide, hypochlorite and nitric oxide (NO). HOCl generates intra-chain sulfinamide bonds; stronger oxidation promotes cross-linked forms that are seen in human atheroma. S100A8 is >200-fold more sensitive to oxidative cross-linking than low-density lipoprotein and may reduce oxidative damage. S100A8 and S100A9 can be S-nitrosylated. S100A8-SNO suppresses mast cell activation and inflammation in the microcirculation and may act as an NO transporter to regulate vessel tone in inflammatory lesions. S100A12 activates mast cells and is a monocyte and mast cell chemoattractant; a G-protein-coupled mechanism may be involved. Structure-function studies are discussed in relation to conservation and divergence of functions in S100A8. S100A12 induces cytokines in mast cells, but not monocytes/macrophages. It forms complexes with Zn(2+) and, by chelating Zn(2+), S100A12 significantly inhibits MMPs. Zn(2+) in S100A12 complexes co-localize with MMP-9 in foam cells in atheroma. In summary, S100A12 has pro-inflammatory properties that are likely to be stable in an oxidative environment, because it lacks Cys and Met residues. Conversely, S100A8 and S100A9 oxidation and S-nitrosylation may have important protective mechanisms in inflammation.
 ...
PMID:Inflammation-associated S100 proteins: new mechanisms that regulate function. 2021 44

Several S100 Ca(2+)-binding proteins are considered damage-associated molecular pattern molecules (DAMPs). They are actively secreted or released from necrotic cells in response to tissue injury or stress and have various functions important in innate immunity. Here, we review several DAMPs, with particular focus on S100A8 and S100A9, which are susceptible to oxidative modifications by various forms of reactive oxygen species. We discuss the unique posttranslational modifications generated in S100A8 by hypochlorite and the likely structural consequences that alter function. We propose that some reversible modifications act as regulatory switches, representing a mechanism to arrest their novel antiinflammatory activities. These may be important in dampening mast cell activation and altering properties of the activated microcirculation to limit leukocyte adhesion, transmigration, and accumulation. S-nitrosylation of S100A8 in the vasculature could regulate nitric oxide transport and contribute to vessel reflow during resolution of inflammation.
 ...
PMID:Oxidative modifications of DAMPs suppress inflammation: the case for S100A8 and S100A9. 2091 39