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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Tsuji
Fumio
F
Research and Development Center, Santen Pharmaceutical Co, Ltd, Ikoma-shi, Nara, Japan. fumio.tsuji@santen.co.jp
Yoshimi
Miwa
M
Katsuta
Osamu
O
Takai
Miwa
M
Ishihara
Katsuhiko
K
Aono
Hiroyuki
H
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005921:Glomerulonephritis / Q000235:genetics / Q000473:pathology; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D007596:Joints / Q000473:pathology; D008221:Lymphoid Tissue / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D009929:Organ Size; D017354:Point Mutation; D013045:Species Specificity; D013154:Spleen / Q000473:pathology; D013264:Stifle / Q000473:pathology
D018501:Antirheumatic Agents; D050822:Cytokine Receptor gp130; D008727:Methotrexate