Essential roles of Toll-like receptor-4 signaling in arthritis induced by type II collagen antibody and LPS.
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-4(lps-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-alpha 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-4(lps-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-4(lps-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-4(lps-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.
Lee
Eun-Kyu
EK
Department of Anatomy and Cell Biology, Institute of Biomedical Science, Hanyang University, Seoul, Korea.
Kang
Sang-Mee
SM
Paik
Doo-Jin
DJ
Kim
Jung Mogg
JM
Youn
Jeehee
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D024043:Collagen Type II / Q000276:immunology* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors