Inhibitory effect of a new anti-rheumatic drug T-614 on costimulatory molecule expression, cytokine production, and antigen presentation by synovial cells.
The present study was undertaken to investigate the immunoregulatory effects of T-614 (3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-o ne) on synovial cells in vitro. Synovial cells were cultured with T-614 in the presence or absence of various cytokines. After incubation, the costimulatory molecule expression on synovial cells and cytokine production in culture supernatants were analyzed by an indirect immunofluorescence method and enzyme-linked immunosorbent assay, respectively. We also examined the effect of T-614 on the function of synovial cells as antigen-presenting cells (APCs). The costimulatory molecules including CD54, CD58, and CD106 were constitutionally expressed on the surface of synovial cells. However, neither CD80 nor CD86 nor CD102 was found on the surface, and these costimulatory molecules could not be induced by any cytokines. T-614 itself did not affect the costimulatory molecule expression and cytokine production of unstimulated synovial cells. The stimulation of synovial cells with interferon-gamma (IFN-gamma), interleukin-1beta, or 12-O-tetradecanoyl phorbol 13-acetate enhanced the expression of costimulatory molecules and the proinflammatory cytokine production of these cells. Both the up-regulated expression of these costimulatory molecules and the enhanced production of proinflammatory cytokines were significantly inhibited by T-614. Autologous T cell proliferation in response to purified protein derivative by IFN-gamma-treated synovial cells was significantly suppressed by T-614. T-614 has considerable immunosuppressive effects on synovial cells by inhibiting the costimulatory molecule expression and cytokine production of these cells and the antigen-specific T cell proliferation mediated by the synovial cells. These results suggest that T-614 plays an important immunoregulatory role in rheumatoid synovial tissues.
Kawakami
A
A
First Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
Tsuboi
M
M
Urayama
S
S
Matsuoka
N
N
Yamasaki
S
S
Hida
A
A
Aoyagi
T
T
Furuichi
I
I
Nakashima
T
T
Migita
K
K
Kawabe
Y
Y
Nakashima
M
M
Origuchi
T
T
Eguchi
K
K
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D018968:CD58 Antigens / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D003864:Depression, Chemical; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D013583:Synovial Membrane / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018501:Antirheumatic Agents; D001578:Benzopyrans; D018968:CD58 Antigens; D016207:Cytokines; D006684:HLA-DR Antigens; D007375:Interleukin-1; D013449:Sulfonamides; D019010:Vascular Cell Adhesion Molecule-1; C077313:T 614; D018799:Intercellular Adhesion Molecule-1; D013755:Tetradecanoylphorbol Acetate