Amino Acids

, Volume 41, Issue 4, pp 821–842 | Cite as

Inflammation-associated S100 proteins: new mechanisms that regulate function

  • Jesse Goyette
  • Carolyn L. GeczyEmail author
Review Article


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 Zn2+ and, by chelating Zn2+, S100A12 significantly inhibits MMPs. Zn2+ 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.


S100 Calgranulins S100A8 S100A9 S100A12 Inflammation Interleukin 10 



Rheumatoid arthritis


Inflammatory bowel disease


Reactive oxygen species


Nitric oxide


Toll-like receptor


Murine S100A8


Murine S100A9


Tumor necrosis factor α


Transforming growth factor β








Cyclo-oxygenase 2


Cyclic adenosine monophosphate

MAP kinase

Mitogen-activated protein kinase


Endothelial cells


Fibroblast growth factor






Peroxisome proliferator-activated receptor-γ


Receptor for advanced glycation end products


Nuclear factor κB


Extracellular newly identified RAGE-binding protein


Advanced glycation end products


Monocyte chemotactic protein 1


Neutrophil immobilizing factor


Nicotinamide adenine dinucleotide phosphate


Nuclear magnetic resonance




Matrix metalloproteinase



The authors acknowledge the National Health and Medical Research Council of Australia for funding and members of the laboratory who contributed to the research discussed in this review, particularly Dr. Kenneth Hsu, Ms. Su Yin Lim, Dr. Zheng Yang, Dr. Weixing Yan and Dr. Mark Raftery and our long-term collaborator, Professor Paul Alewood.


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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Centre for Infection and Inflammation Research, School of Medical SciencesUniversity of New South WalesSydneyAustralia

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