Inflammation-associated S100 proteins: new mechanisms that regulate function.
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.
Goyette
Jesse
J
Centre for Infection and Inflammation Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
Geczy
Carolyn L
CL
D000595:Amino Acid Sequence; D000818:Animals; D040501:Calgranulin A / Q000235:genetics* / Q000378:metabolism*; D040502:Calgranulin B / Q000235:genetics* / Q000378:metabolism*; D002465:Cell Movement; D005786:Gene Expression Regulation; D007249:Inflammation / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D009418:S100 Proteins / Q000378:metabolism; D000067616:S100A12 Protein; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D040501:Calgranulin A; D040502:Calgranulin B; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D015032:Zinc