Abstract
S100A8 and S100A9, two Ca2+-binding proteins of the S100 family, are secreted as a heterodimeric complex (S100A8/A9) from neutrophils and monocytes/macrophages. Serum and synovial fluid levels of S100A8, S100A9, and S100A8/A9 were all higher in patients with rheumatoid arthritis (RA) than in patients with osteoarthritis (OA), with the S100A8/A9 heterodimer being prevalent. By two-color immunofluorescence labeling, S100A8/A9 antigens were found to be expressed mainly by infiltrating CD68+ macrophages in RA synovial tissue (ST). Isolated ST cells from patients with RA spontaneously released larger amounts of S100A8/A9 protein than did the cells from patients with OA. S100A8/A9 complexes, as well as S100A9 homodimers, stimulated the production of proinflammatory cytokines, such as tumor necrosis factor alpha, by purified monocytes and in vitro-differentiated macrophages. S100A8/A9-mediated cytokine production was suppressed significantly by p38 mitogen-activated protein kinase (MAPK) inhibitors and almost completely by nuclear factor kappa B (NF-κB) inhibitors. NF-κB activation was induced in S100A8/A9-stimulated monocytes, but this activity was not inhibited by p38 MAPK inhibitors. These results indicate that the S100A8/A9 heterodimer, secreted extracellularly from activated tissue macrophages, may amplify proinflammatory cytokine responses through activation of NF-κB and p38 MAPK pathways in RA.
Highlights
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
Increased concentrations of the S100A8/A9 heterodimer in serum and synovial fluid (SF) from patients with rheumatoid arthritis (RA) Concentrations of S100A8, S100A9, and the S100A8/A9 heterodimer in paired serum and SF samples obtained from 17 patients with RA and 17 patients with OA were compared by enzymelinked immunosorbent assay (ELISA)
The levels of S100A8, S100A9, and S100A8/A9 in serum and SF were all significantly increased in patients with RA (20.4 ± 7.8 ng/ml, 2.9 ± 0.3 ng/ml, and 38.9 ± 6.0 mg/ml in serum and 65.3 ± 23.4 ng/ml, 27.9 ± 4.5 ng/ml, and 54.8 ± 7.2 μg/ml in SF, respectively) as compared with patients with OA (7.0 ± 3.0 ng/ml, 0.9 ± 0.1 ng/ml, and 16.8 ± 4.8 μg/ ml in serum and 5.1 ± 2.2 ng/ml, 3.6 ± 0.4 ng/ml, and 7.3 ± 4.5 μg/ml in SF, respectively) (Figure 1)
Summary
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 designated as migration inhibitory factor- or myeloid-related protein-8 (MRP8) and MRP14, or calgranulin A and B, respectively [1,2,3]. RAGE, a scavenger receptor belonging to the immunoglobulin (Ig) family that signals to the nuclear factor kappa B (NF-κB) pathway, was identified as a functional receptor for the S100A12 protein [14]. Structural similarities between S100A12 and other S100 proteins [3] and the binding of S100B and S100A12 to RAGE [1] suggest that RAGE may be a general receptor for the S100 family of proteins
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