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HIDEYUKI KOBAYASHI, SHIRO OHSHIMA, KATSUHIRO NISHIOKA, NORIHIKO YAMAGUCHI, MITSUKO UMESHITA-SASAI, TAEKO ISHII, TORU MIMA, TADAMITSU KISHIMOTO, ICHIRO KAWASE, and YUKIHIKO SAEKI

ABSTRACT.

Objective. To investigate the role of bone marrow cells (BMC) in the induction of antigen induced arthritis (AIA), the expression of 3 major proinflammatory cytokines, interleukin 1ß (IL-1ß), tumor necrosis factor-a (TNF-a), and IL-6, was examined in the bone marrow (BM) of mice with AIA. We also examined whether AIA could be transferred by bone marrow transplantation (BMT).

Methods. Expression of IL-1ß, TNF-a, and IL-6 in BMC was assessed by immunohistochemistry throughout the course of AIA. BMT experiments were performed using 2 different mouse genotypes, wild type (IL-6+/+) and IL-6 deficient (IL-6-/-) mice, as a donor. The gradation of AIA was evaluated histologically.

Results. IL-6 was highly expressed in the BM at induction as well as during progression of AIA, while TNF-a showed a marginal expression, and no significant expression of IL-1ß was detected throughout the course of AIA. In BMT experiments, all irradiated IL-6+/+ mice developed typical AIA by transplantation of BMC from immunized IL-6+/+ mice, whereas almost no irradiated IL-6+/+ mice transplanted with BMC from the immunized IL-6-/- mice developed definite arthritis.

Conclusion. These results suggest that BMC play a critical role and IL-6 is a key cytokine for the induction and progression of AIA. There may be clinical benefits in the blockade of IL-6 and BMT in the treatment of rheumatoid arthritis. (J Rheumatol 2002;29:1176-82)

Key Indexing Terms:

RHEUMATOID ARTHRITIS
IL-6
KNOCKOUT MICE
IMMUNOHISTOCHEMISTRY
BONE MARROW CELLS

Supported in part by grants from the Ministry of Education, Science, and Culture, and the Ministry of Health and Welfare of Japan.

H. Kobayashi, BS, Department of Molecular Medicine, Osaka University Medical School and Tokyo Research Laboratories, Kowa Co.; S. Ohshima, MD; K. Nishioka, MD; N. Yamaguchi, MD; M. Umeshita-Sasai, MD; T. Ishii, MD; T. Mima, MD, Department of Molecular Medicine, Osaka University Medical School; T. Kishimoto, MD, Osaka University; I. Kawase, MD; Y. Saeki, MD, Department of Molecular Medicine, Osaka University Medical School.

Address reprint requests to Dr. Y. Saeki, Department of Molecular Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan. E-mail: saekiy@imed3.med.osaka-u.ac.jp

Submitted August 13, 2001; revision accepted December 31, 2001.