The Journal of Experimental Medicine
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Published online 30 September 2002 doi:10.1084/jem.20020619
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© Rockefeller University Press, 0022-1007/2002/10/979/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 7, October 7, 2002 979-990

A Point Mutation of Tyr-759 in Interleukin 6 Family Cytokine Receptor Subunit gp130 Causes Autoimmune Arthritis

Toru Atsumi1,5, Katsuhiko Ishihara1,4, Daisuke Kamimura1, Hideto Ikushima1, Takuya Ohtani1, Seiichi Hirota2, Hideyuki Kobayashi6, Sung-Joo Park1, Yukihiko Saeki3, Yukihiko Kitamura2 and Toshio Hirano1,4,5

1 Department of Molecular Oncology (C7), Graduate School of Medicine
2 Department of Pathology (C2), Graduate School of Medicine
3 Department of Molecular Medicine (C4), Graduate School of Medicine
4 Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan
5 Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology (RCAI), Yokohama, Kanagawa 230-0045, Japan
6 Tokyo Research Laboratories, Kowa Co., Ltd, Higashi-murayama, Tokyo 189-0022, Japan

Address correspondence to T. Hirano, Dept. of Molecular Oncology, C-7, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3880; Fax: 81-6-6879-3889; E-mail: hirano{at}molonc.med.osaka-u.ac.jp

We generated a mouse line in which the src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130F759/F759). The gp130F759/F759 mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130F759/F759 T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.

Key Words: IL-6 • rheumatoid arthritis • gp130 • SHP-2 • STAT-3


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