LIGHT Induces Cell Proliferation and Inflammatory Responses of Rheumatoid Arthritis Synovial Fibroblasts via Lymphotoxin β Receptor

SATORU ISHIDA, SHOJI YAMANE, SAORI NAKANO, TOSHIHITO MORI, TAKUO JUJI, NAOSHI FUKUI, TSUNETOSHI ITOH, TAKAHIRO OCHI, and RYUJI SUZUKI

ABSTRACT.

Objective. To investigate the effects of LIGHT (lymphotoxin-like, exhibits inducible expression and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes) on the proliferation and gene expression of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).

Methods. We measured LIGHT levels in RA synovial fluids (SF) by ELISA, and compared them with those in osteoarthritis (OA) SF. Levels of LIGHT and its receptors in RA-FLS and synovium were assessed using real-time quantitative polymerase chain reaction (PCR). RA-FLS proliferation was examined by a bromodeoxyuridine assay. Expression of intercellular adhesion molecule-1 (ICAM-1) and several chemokines, such as interleukin 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1a (MIP-1a), was examined by real-time quantitative PCR, ELISA, and flow cytometry. The effects of LIGHT on nuclear factor-κB (NF-κB) activation were investigated using immunofluorescence and Western blotting.

Results. LIGHT was upregulated in both SF and synovium of RA patients compared with OA patients. Herpes virus entry mediator (HVEM) and lymphotoxin ß receptor (LTßR), but not LIGHT, were detected in RA-FLS. LIGHT significantly promoted RA-FLS proliferation and induced expression of MCP-1, IL-8, MIP-1a, and ICAM-1 by RA-FLS. As well, LTßR small interfering RNA (siRNA), but not HVEM siRNA, inhibited these effects of LIGHT. LIGHT induced IκBa degradation and NF-κB translocation, and a NF-κB inhibitor suppressed the effects of LIGHT on RA-FLS.

Conclusion. Our findings suggest that LIGHT signaling via LTßR plays an important role in the pathogenesis of RA by affecting key processes such as the proliferation and activation of RA-FLS. Regulation of LIGHT-LTßR signaling may represent a new therapeutic target for RA treatment. (First Release April 15 2008; J Rheumatol 2008;35:960-8)

Key Indexing Terms:

RHEUMATOID ARTHRITIS
INFLAMMATION
SYNOVIOCYTES

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From the Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Kanagawa; Discovery Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka; and Department of Immunology and Embryology, Tohoku University School of Medicine, Aoba-ku, Sendai, Japan.

S. Ishida, MSc; S. Yamane, PhD, Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Discovery Research Laboratories, Shionogi & Co., Ltd.; S. Nakano, BSc; T. Mori, MD, PhD; T. Juji, MD, PhD; N. Fukui, MD, PhD, Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital; T. Itoh, MD, PhD, Department of Immunology and Embryology, Tohoku University School of Medicine; T. Ochi, MD, PhD; R. Suzuki, DVM, PhD, Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital.

Address reprint requests to S. Ishida, Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Sakuradai 18-1, Sagamihara, Kanagawa, 228-8522, Japan. E-mail: satoru.ishida@shionogi.co.jp
Accepted for publication January 10, 2008.

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