TY - JOUR
T1 - Semaphorin 4D contributes to rheumatoid arthritis by inducing inflammatory cytokine production
T2 - Pathogenic and therapeutic implications
AU - Yoshida, Yuji
AU - Ogata, Atsushi
AU - Kang, Sujin
AU - Ebina, Kousuke
AU - Shi, Kenrin
AU - Nojima, Satoshi
AU - Kimura, Tetsuya
AU - Ito, Daisuke
AU - Morimoto, Keiko
AU - Nishide, Masayuki
AU - Hosokawa, Takashi
AU - Hirano, Toru
AU - Shima, Yoshihito
AU - Narazaki, Masashi
AU - Tsuboi, Hideki
AU - Saeki, Yukihiko
AU - Tomita, Tetsuya
AU - Tanaka, Toshio
AU - Kumanogoh, Atsushi
N1 - Publisher Copyright:
© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - Objective Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA). Methods Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme-linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS-4-treated monocytic cell line (THP-1 cells). The efficacy of anti-Sema4D antibody was evaluated in mice with collagen-induced arthritis (CIA). Results Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D-expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS-4 cleaved cell surface Sema4D to generate sSema4D in THP-1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) production from CD14+ monocytes. IL-6 and TNFα induced ADAMTS-4 expression in synovial cells. Treatment with an anti-Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA. Conclusion A positive feedback loop involving sSema4D/IL-6 and TNFα/ADAMTS-4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti-Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA.
AB - Objective Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA). Methods Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme-linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS-4-treated monocytic cell line (THP-1 cells). The efficacy of anti-Sema4D antibody was evaluated in mice with collagen-induced arthritis (CIA). Results Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D-expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS-4 cleaved cell surface Sema4D to generate sSema4D in THP-1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) production from CD14+ monocytes. IL-6 and TNFα induced ADAMTS-4 expression in synovial cells. Treatment with an anti-Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA. Conclusion A positive feedback loop involving sSema4D/IL-6 and TNFα/ADAMTS-4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti-Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA.
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U2 - 10.1002/art.39086
DO - 10.1002/art.39086
M3 - Article
C2 - 25707877
AN - SCOPUS:84929864374
VL - 67
SP - 1481
EP - 1490
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
SN - 2326-5191
IS - 6
ER -