OBJECTIVE: To compare the effects of tenidap, a new antirheumatic drug, with a nonsteroidal anti-inflammatory drug, naproxen, on the synthesis and expression of interleukin-1 beta (IL-1 beta), tumor necrosis factor (TNF-alpha), and interleukin-6 (IL-6) in rheumatoid synovium. METHODS: Human synovial membrane explants from patients with rheumatoid arthritis (RA) were incubated in the absence or presence of 20 micrograms/ml lipopolysaccharides (LPS) and tenidap at 50, 20 (therapeutic concentration), and 5 micrograms/ml or naproxen at 90 (therapeutic concentration) and 30 micrograms/ml. The levels of IL-1 beta, TNF-alpha, and IL-6 in the culture medium were measured by specific enzyme linked immunosorbent assays. The cytokine mRNA levels were quantitated by Northern blotting. RESULTS: In the absence of LPS, tenidap at 20 micrograms/ml produced a significant (p < 0.04) decrease in the IL-1 synthesis level. Under LPS stimulation, IL-1 beta synthesis was inhibited by tenidap at all concentrations tested (p < 0.01) and by naproxen at only 90 micrograms/ml (p < 0.01). Very small amounts of TNF-alpha could be detected only when the synovial membranes were stimulated with LPS. Tenidap significantly reduced LPS stimulated TNF-alpha synthesis; the maximum inhibition was noted at 20 micrograms/ml (69%, p < 0.002). Naproxen, at 90 micrograms/ml, reduced TNF-alpha synthesis by about 40% (p < 0.03) and values were similar to those with subtherapeutic concentrations (5 micrograms/ml) of tenidap. The spontaneous and LPS induced synthesis of IL-6 was significantly inhibited by tenidap at all concentrations tested, whereas neither concentration of naproxen demonstrated a significant effect. Tenidap induced a somewhat similar reduction pattern of IL-1 beta and IL-6 mRNA to that observed for cytokine synthesis. Naproxen only slightly reduced the LPS induced expression of IL-6, while enhancing the IL-1 beta expression. CONCLUSION: Tenidap and naproxen showed differences in their effects on cytokine synthesis and mRNA expression. Tenidap, at the therapeutic concentration, was most clearly differentiated from naproxen by its inhibition of IL-6, but was also a more potent modulator of IL-1 beta and TNF-alpha in RA synovial explants. The significance of these findings lies in the possible therapeutic benefit of proinflammatory cytokine suppression in joint disease.
OBJECTIVE: To compare the effects of tenidap, a new antirheumatic drug, with a nonsteroidal anti-inflammatory drug, naproxen, on the synthesis and expression of interleukin-1 beta (IL-1 beta), tumor necrosis factor (TNF-alpha), and interleukin-6 (IL-6) in rheumatoid synovium. METHODS:Human synovial membrane explants from patients with rheumatoid arthritis (RA) were incubated in the absence or presence of 20 micrograms/ml lipopolysaccharides (LPS) and tenidap at 50, 20 (therapeutic concentration), and 5 micrograms/ml or naproxen at 90 (therapeutic concentration) and 30 micrograms/ml. The levels of IL-1 beta, TNF-alpha, and IL-6 in the culture medium were measured by specific enzyme linked immunosorbent assays. The cytokine mRNA levels were quantitated by Northern blotting. RESULTS: In the absence of LPS, tenidap at 20 micrograms/ml produced a significant (p < 0.04) decrease in the IL-1 synthesis level. Under LPS stimulation, IL-1 beta synthesis was inhibited by tenidap at all concentrations tested (p < 0.01) and by naproxen at only 90 micrograms/ml (p < 0.01). Very small amounts of TNF-alpha could be detected only when the synovial membranes were stimulated with LPS. Tenidap significantly reduced LPS stimulated TNF-alpha synthesis; the maximum inhibition was noted at 20 micrograms/ml (69%, p < 0.002). Naproxen, at 90 micrograms/ml, reduced TNF-alpha synthesis by about 40% (p < 0.03) and values were similar to those with subtherapeutic concentrations (5 micrograms/ml) of tenidap. The spontaneous and LPS induced synthesis of IL-6 was significantly inhibited by tenidap at all concentrations tested, whereas neither concentration of naproxen demonstrated a significant effect. Tenidap induced a somewhat similar reduction pattern of IL-1 beta and IL-6 mRNA to that observed for cytokine synthesis. Naproxen only slightly reduced the LPS induced expression of IL-6, while enhancing the IL-1 beta expression. CONCLUSION: Tenidap and naproxen showed differences in their effects on cytokine synthesis and mRNA expression. Tenidap, at the therapeutic concentration, was most clearly differentiated from naproxen by its inhibition of IL-6, but was also a more potent modulator of IL-1 beta and TNF-alpha in RA synovial explants. The significance of these findings lies in the possible therapeutic benefit of proinflammatory cytokine suppression in joint disease.