The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis

S100A8 and S100A9 are two members of the S100 protein family that are characterized by the presence of two Ca2+-binding sites of the EF-hand type. These proteins are also designated as migration inhibitory factor- or myeloid-related protein-8 (MRP8) and MRP14, or calgranulin A and B, respectively [1-3]. Most members of the S100 family exist in the form of homodimers or heterodimers within cells and interact with several effector proteins mostly in a Ca2+-dependent manner, thereby regulating enzyme activities, the dynamics of cytoskeleton constituents, cell growth and differentiation, and Ca2+ homeostasis [1]. S100A8 and S100A9 are predominantly expressed in cells of the myelomonocytic lineage; both proteins are present at high concentrations in the cytoplasm of neutrophils and monocytes, and the S100A8/A9 heterodimer is translocated to membrane and cytoskeletal structures upon activation [4-6]. Intracellular S100A8/A9 complexes play an important role in myeloid cell maturation, cell trafficking, and arachidonic acid (AA) metabolism [2].S100A8 and S100A9 are secreted as complexes from neutrophils and monocytes after activation of protein kinase C in a novel pathway requiring an intact microtubule network [7]. High levels of the proteins have been found in the extracellular milieu during inflammatory conditions such as rheumatoid arthritis (RA) [2,3]. The S100A8/A9 heterodimer, originally identified as an antimicrobial protein, exhibits cytokine-like functions in the local environment, most notably enhancing leukocyte recruitment to inflammatory sites and AA transportation to its target cells [8-10]. However, the nature of surface receptors for S100A8/A9 and its signaling pathways has not yet been fully elucidated. The soluble S100A8/A9 complex binds to the cell surface of endothelial cells by interacting with specific binding sites such as heparin sulfate proteoglycans and novel carboxylated glycans [11,12]. In addition, CD36 and the receptor for advanced glycation e