Point mutation of tyrosine 759 of the IL-6 family cytokine receptor, gp130, augments collagen-induced arthritis in DBA/1J mice

• Published in: BMC musculoskeletal disorders 2009-02, Vol.10 (1), p.23-23, Article 23
• Main Authors: Tsuji, Fumio, Yoshimi, Miwa, Katsuta, Osamu, Takai, Miwa, Ishihara, Katsuhiko, Aono, Hiroyuki
• Format: Article
• Language: English
• Subjects: Animals; Antirheumatic Agents - pharmacology; Arthritis, Experimental - genetics; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Cell receptors; Cytokine Receptor gp130 - genetics; Gene mutations; Genetic aspects; Genetic Predisposition to Disease; Glomerulonephritis - genetics; Glomerulonephritis - pathology; Health aspects; Hyperplasia - genetics; Hyperplasia - pathology; Joints - pathology; Lymphoid Tissue - pathology; Methotrexate - pharmacology; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Mutant Strains; Organ Size; Physiological aspects; Point Mutation; Rheumatoid arthritis; Risk factors; Species Specificity; Spleen - pathology; Stifle - pathology
• ISSN: 1471-2474; 1471-2474
• DOI: 10.1186/1471-2474-10-23

Knock-in mice (gp130F759) with a Y759F point mutation in gp130, a signal transducing receptor subunit shared by members of the IL-6 cytokine family, show sustained activation of STAT3, enhanced acute-phase or immune responses, and autoimmune arthritis. We conducted a detailed analysis of collagen-induced arthritis (CIA) in gp130F759 with a DBA/1J background (D/J.gp130F759). We backcrossed gp130F759 to C57BL/6 and DBA/1J, and compared the pathologic changes, including occurrence of arthritis, in the two distinct genetic backgrounds. We analyzed CIA in D/J.gp130F759 and investigated the effects of methotrexate (MTX) on CIA. C57BL/6 background gp130F759 mice, but not D/J.gp130F759, spontaneously developed polyarthritis and glomerulonephritis. On the other hand, keratitis of the eyes only developed in D/J.gp130F759, indicating the influence of genetic background on disease development in gp130F759 mice. Resistance of the DBA/1J background against spontaneous arthritis urged us to examine CIA in D/J.gp130F759. CIA in D/J.gp130F759 was more severe, with greater bone destruction, than the control mice. After collagen immunization, splenomegaly and serum levels of rheumatoid factor and anti-DNA antibody were augmented in D/J.gp130F759. Bio-Plex analysis of serum cytokines revealed increased IL-12p40 and PDGF-BB before immunization, and increased levels of IFN-gamma, IL-17, TNF-alpha, IL-9, and MIP-1beta 8 days after the booster dose. IL-6 and PDGF-BB in D/J.gp130F759 showed distinct kinetics from the other cytokines; higher levels were observed after arthritis development. MTX partially attenuated the development of arthritis and inhibited bone destruction in D/J.gp130F759, with reduction of anti-type II collagen antibody levels, suggesting that MTX mainly affects antigen-specific immune responses in CIA. The Tyr-759 point mutation of the IL-6 family cytokine receptor subunit, gp130, caused autoimmune disease, and this was also influenced by the genetic background. CIA in D/J.gp130F759 is useful for evaluating drugs in a relatively short period because sustained activation of STAT3 may enhance the disease symptoms.