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Open Access Highly Accessed Research article

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

Katsue Sunahori1, Masahiro Yamamura1*, Jiro Yamana1, Kouji Takasugi1, Masanori Kawashima1, Hiroshi Yamamoto2, Walter J Chazin3, Yuichi Nakatani4, Satoru Yui4 and Hirofumi Makino1

Author Affiliations

1 Department of Medicine and Clinical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan

2 Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan

3 Department of Biochemistry and Physics, Center for Structural Biology, Vanderbilt University, 465 21st Avenue, Nashville, TN 87232-8725, USA

4 Faculty of Pharmaceutical Sciences, Teikyo University, 1091-1 Sagamiko, Tsukui-gun, Kanagawa 199-0195, Japan

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Arthritis Research & Therapy 2006, 8:R69  doi:10.1186/ar1939

Published: 13 April 2006

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.