Collagen-induced arthritis (CIA) is an animal model for rheumatoid arthritis (RA). Lipopolysaccharide (LPS) is known to accelerate CIA; however, the pathogenetic mechanisms are not yet fully understood. In this study, type II collagen (CII)-immunized mice were found to have marked increases in degree of expression of mRNA of inflammatory mediators such as tumor necrosis factor alpha (TNF-a), interleukin (IL)-1b, and macrophage inflammatory protein-2 (MIP-2) in their arthritic paws and of serum anti-CII antibody concentration before the onset of arthritis induced by LPS injection. The gene expression was rapid and continuous after direct activation of nuclear factor kB. The amounts of mRNA of TNF-a, IL-1b, and MIP-2, as well as of matrix metalloproteinases and the receptor activator of nuclear factor kB ligand, increased with the development of arthritis, correlated positively with clinical severity and corresponded with histopathological changes. Moreover, anti-TNF-a neutralizing antibody inhibited the development of LPS-accelerated CIA and a single injection of recombinant mouse TNF-a induced increases in anti-CII antibody concentrations, suggesting TNF-a may contribute to the development of arthritis by both initiation of inflammation and production of autoantibodies. These data suggest that exacerbation of RA by LPS is associated with rapid and continuous production of inflammatory mediators and autoantibodies.Key words anti-type II collagen antibody, collagen-induced arthritis, inflammatory mediators, lipopolysaccharide.Rheumatoid arthritis is a systemic autoimmune disease that is characterized by chronic inflammation of joints, leading to synovial hyperplasia, infiltration of leukocytes and progressive destruction of cartilage and bone (1). Various humoral factors are involved in the development of RA. One of these is autoantibodies, which activate complement systems by formation of immune complexes in combination with self-antigens and induce recruitment of inflammatory cells into synovium (1, 2). Another important factor is inflammatory mediators such as Correspondence Shinji Tanaka, Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Tel: þ81 3 3492 3131; fax: þ81 3 5740 3644; email: tanaka.shinji.fv@daiichisankyo.co.jp List of Abbreviations: CIA, collagen-induced arthritis; CII, type II collagen; E. coli, Escherichia coli; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IkBa, inhibitor of nuclear factor kB alpha; IL, interleukin; LPS, lipopolysaccharide; LPS-CIA, lipopolysaccharide-accelerated collageninduced arthritis; MIP-2, macrophage inflammatory protein-2; MMP, matrix metalloproteinase; ND, not detected; NF-kB, nuclear factor kB; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor kB ligand; SEM, standard error of the mean; TLR, Toll-like receptor; TNF-a, tumor necrosis factor alpha.