International Immunology Advance Access originally published online on January 31, 2005
International Immunology 2005 17(3):325-333; doi:10.1093/intimm/dxh212
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Essential roles of Toll-like receptor-4 signaling in arthritis induced by type II collagen antibody and LPS
1 Department of Anatomy and Cell Biology, Institute of Biomedical Science and 2 Department of Microbiology, College of Medicine, Hanyang University, Seoul 133-791, Korea
Correspondence to: J. Youn; E-mail: jhyoun{at}hanyang.ac.kr
Although bacterial LPS has been used to boost the susceptibility to antibody-induced arthritis, the mechanism of the action of LPS remains to be clarified. We investigated whether signals triggered by Toll-like receptor (TLR)-4 mediate the effects of LPS in the context of anti-type II collagen-induced arthritis. The mice defective in the Tlr-4 gene (Tlr-4lps-d) were markedly less susceptible than wild type to arthritis, as manifested in arthritic index, incidence and synovitis. Levels of the pro-inflammatory mediators, tumor necrosis factor-
and cyclooxygenase-2, in their synovial tissue were also much lower. Serum C3 deposition through the alternative pathway and de novo synthesis of C3 were lower in the Tlr-4lps-d mice in the post-acute phase, pointing to an influence of TLR-4 signals on the turnover rate of complement cascades. T cells from the Tlr-4lps-d mice failed to proliferate in response to an auto-antigen, glucose-6-phosphate isomerase (GPI), unlike those from wild-type mice, and the serum level of GPI-specific IgG antibody was significantly lower than in the wild-type mice. Interestingly, type 2 responses, such as GPI-specific IgG1 and IL-4 production, were up-regulated in the Tlr-4lps-d mice. Taken together, our data suggest that the TLR-4 signaling pathway plays an essential role in the initiation and progression of auto-antibody/LPS-triggered arthritis by inducing pro-inflammatory mediators, C3 deposition, auto-antigen-specific adaptive immune responses and immune deviation between type 1 and type 2 responses.
Keywords: antibody-induced arthritis, LPS, Th1/Th2, Toll-like receptor-4, type II collagen
Transmitting editor: K. Yamamoto
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