The S100A8 and S100A9 Proteins are Attractive Targets to Modulate Inflammation

Claus Kerkhoff

doi:10.2174/187152307781368247

Abstract

The members of the S100 protein family compose a multigenic family of non-ubiquitous cytoplasmic Ca2+- binding proteins of EF-hand type that are differentially expressed in a wide variety of cell types. In particular, S100A8 and S100A9 also known as calgranulins are abundant in myeloid cells. Profound expression of S100A8 and S100A9 has been reported in various disorders, such as rheumatoid arthritis, inflammatory bowel disease and vasculitis. Thus, the S100/calgranulins are associated with inflammatory disorders as they are secreted from phagocytes upon cellular activation and track disease activity. In addition to their abundance in myeloid cells S100A8 and S100A9 can also be found in the epidermis upon response to stress. S100A8 and S100A9 form heteromeric protein complexes that are located in the cytosol of resting phagocytes and that can exhibit two independent translocation pathways upon cellular activation. Therefore, it has been assumed that membrane- associated and soluble S100A8/A9 may have distinct cellular functions. Recent data indicate that intracellular S100A8/A9 might be involved in the (phagocyte) NADPH oxidase activation, whereas the secreted form exerts antimicrobial properties and induces apoptotic and cytotoxic activities. The S100 proteins are suggested to bind to the receptor for advanced glycation end products (RAGE), and the RAGE/S100 interaction has been considered to represent a novel proinflammatory axis involved in several inflammatory diseases, thereby offering an attractive model to explain how RAGE and its proinflammatory ligands contribute to the pathophysiology of several inflammatory diseases. This review addresses recent developments regarding the functional role of the two S100 proteins in inflammation. In view of the current knowledge the author will show that these S100-proteins are reliable clinical parameters as well as attractive targets to modulate inflammation.

Keywords: migration inhibitory factor, S100 genes, MRP regulatory element, Translocation Pathways, NADPH oxidase

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