Point Mutation of Tyrosine 759 of the IL-6 Family Cytokine Receptor, Gp130, Augments Collagen-induced Arthritis in DBA/1J Mice

Overview

Journal BMC Musculoskelet Disord

Publisher Biomed Central

Specialties Orthopedics
Physiology

Date 2009 Feb 21

PMID 19228423

Citations 8

Authors

Fumio Tsuji

Miwa Yoshimi

Osamu Katsuta

Miwa Takai

Katsuhiko Ishihara

Hiroyuki Aono

Affiliations

Soon will be listed here.

Abstract

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.

Conclusion: 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.

Citing Articles

New Studies of Pathogenesis of Rheumatoid Arthritis with Collagen-Induced and Collagen Antibody-Induced Arthritis Models: New Insight Involving Bacteria Flora.

Hashida R, Shimozuru Y, Chang J, Agosto-Marlin I, Waritani T, Terato K Autoimmune Dis. 2021; 2021:7385106.

PMID: 33833871 PMC: 8016593. DOI: 10.1155/2021/7385106.

Ameliorated Autoimmune Arthritis and Impaired B Cell Receptor-Mediated Ca Influx in Nkx2-3 Knock-out Mice.

Khanfar E, Olasz K, Gabris F, Gajdocsi E, Botz B, Kiss T Int J Mol Sci. 2020; 21(17).

PMID: 32859051 PMC: 7503974. DOI: 10.3390/ijms21176162.

Pien Tze Huang alleviate the joint inflammation in collagen-induced arthritis mice.

Deng Y, Luo H, Shu J, Shu H, Lu C, Zhao N Chin Med. 2020; 15:30.

PMID: 32256686 PMC: 7106633. DOI: 10.1186/s13020-020-00311-3.

Daily oral administration of low-dose methotrexate has greater antirheumatic effects in collagen-induced arthritis rats.

Koyama A, Tanaka A, To H J Pharm Pharmacol. 2017; 69(9):1145-1154.

PMID: 28560778 PMC: 5575561. DOI: 10.1111/jphp.12752.

Recent advances in neutralizing the IL-6 pathway in arthritis.

Malemud C Open Access Rheumatol. 2009; 1:133-150.

PMID: 27789987 PMC: 5074717. DOI: 10.2147/oarrr.s6266.

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