In vitro effects of 2 antirheumatic drugs on the synthesis and expression of proinflammatory cytokines in synovial membranes from patients with rheumatoid arthritis.
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.


CONCLUSIONS
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.
Ounissi-Benkalha
H
H
Department of Medicine, Notre-Dame Hospital, Montréal, Canada.
Pelletier
J P
JP
Tardif
G
G
Mineau
F
F
Jolicoeur
F C
FC
Ranger
P
P
Martel-Pelletier
J
J
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D015152:Blotting, Northern; D016207:Cytokines / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000494:pharmacology*; D007375:Interleukin-1 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009288:Naproxen / Q000494:pharmacology*; D000078183:Oxindoles; D013583:Synovial Membrane / Q000187:drug effects / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D016207:Cytokines; D007211:Indoles; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000078183:Oxindoles; D014409:Tumor Necrosis Factor-alpha; D009288:Naproxen; C062866:tenidap