Antiinflammatory Mediator Lipoxin A4 and Its Receptor in Synovitis of Patients with Rheumatoid Arthritis

ATSUSHI HASHIMOTO, IZUMI HAYASHI, YOUSUKE MURAKAMI, YOSHINORI SATO, HIDERO KITASATO, REIKO MATSUSHITA, NOBUKO IIZUKA, KEN URABE, MORITOSHI ITOMAN, SHUNSEI HIROHATA, and HIRAHITO ENDO

ABSTRACT.

Objective. To evaluate the role of an antiinflammatory lipid mediator, lipoxin A₄ (LXA₄), in inflammatory arthritis, we measured the level of LXA₄ in synovial fluid and lipoxin A₄ receptor (ALX) expression in synovial tissues obtained from patients with rheumatoid arthritis (RA) and osteoarthritis (OA).

Methods. Levels of LXA₄ and its analog (15-epi-LXA₄) in synovial fluid from 30 patients with RA and 15 patients with OA were measured by a specific ELISA. Reverse transcription-polymerase chain reaction (RT-PCR), real-time quantitative PCR, and in situ hybridization were performed to detect mRNA for ALX and 15-LOX, and LXA₄ synthetase, in synovial tissues from 20 patients with RA and 10 patients with OA.

Results. Both LXA₄ and 15-epi-LXA₄ showed significantly higher levels in RA synovial fluid (10.34 ± 14.12 ng/ml for LXA₄) than OA synovial fluid (0.66 ± 0.77 ng/ml for LXA₄). Logarithmic concentration of LXA₄ was significantly correlated with that of leukotriene B₄ and prostaglandin E₂ in RA and OA synovial fluids. Expressions of ALX and 15-LOX mRNA were stronger in RA synovium than OA synovium. Expression of mRNA for interleukin 13 (IL-13), which induces 15-LOX, was significantly stronger in RA synovium than OA synovium.

Conclusion. ALX is an important target of LXA₄ in synovial tissues of patients with RA. 15-LOX induced by IL-13 might regulate the production of LXA₄ to have an antiinflammatory effect against proinflammatory lipid mediators in inflamed joints. These findings could lead to the development of new therapy for inflammatory arthritis such as RA. (First Release Oct 1 2007; J Rheumatol 2007;34:2144-53)

Key Indexing Terms:

RHEUMATOID ARTHRITIS
LIPOXIN A₄
LIPOXIN
INFLAMMATION

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From the Department of Rheumatology and Infectious Diseases and Department of Orthopedics, Kitasato University School of Medicine; Department of Microbiology, Kitasato University School of Allied Health Sciences, Kanagawa; Department of Pathophysiology, Nihon Pharmaceutical University, Saitama; Department of Pathology, Research Institute, International Medical Center of Japan; and Department of Medicine and Rheumatology, Tokyo Medical and Dental University, Tokyo, Japan.

Supported in part by grants-in-aid from the Japanese Ministry of Education, Science, and Sports.

A. Hashimoto, MD, PhD, Lecturer; R. Matsushita, MD, Research Associate; N. Iizuka, MD, Research Associate; S. Hirohata, MD, Professor; H. Endo, MD, PhD, Associate Professor, Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine; I. Hayashi, Professor, Department of Pathophysiology, Nihon Pharmaceutical University; Y. Murakami, PhD, Research Resident, Department of Medicine and Rheumatology, Tokyo Medical and Dental University; Y. Sato, PhD, Research Fellow, Department of Pathology, Research Institute, International Medical Center of Japan; H. Kitasato, MD, Professor, Department of Microbiology, Kitasato University School of Allied Health Science; K. Urabe, MD, PhD, Associate Professor; M. Itoman, MD, Professor, Department of Orthopedics, Kitasato University School of Medicine.

Address reprint requests to Dr. A. Hashimoto, Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-855, Japan. E-mail: hashi@med.kitasato-u.ac.jp

Accepted for publication July 24, 2007.

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