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 wets undertaken to investigate the Immunoregulatory effec ts of T-614 (3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran- 4-one) on synovial cells in vitro. Synovial cells were cultured with T-614 in the presence or absence of various cytokines. After incubation, the cost imulatory 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 cel ls (APCs). The costimulatory molecules Including CD54, CD58, and CD106 were constitutionally expressed on the surface of synovial cells. However, neit her CD80 nor CD86 nor CD102 was found on the surface, and these costimulato ry molecules could not be induced by any cytokines. T-614 itself did not af fect the costimulatory molecule expression and cytokine production of unsti mulated synovial cells. The stimulation of synovial cells with interferon-g amma (IFN-gamma), interleukin-1 beta, or 12-O-tetradecanoyl phorbol 13-acet ate enhanced the expression of costimulatory molecules and the proinflammat ory cytokine production of these cells. Both the up-regulated expression of these costimulatory molecules and the enhanced production of proinflammato ry cytokines were significantly inhibited by T-614. Autologous T cell proli feration in response to purified protein derivative by IFN-gamma-treated sy novial 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 result s suggest that T-614 plays an important immunoregulatory role in rheumatoid synovial tissues.