TENIDAP DECREASES IL-8 AND MONOCYTE CHEMOTACTIC PEPTIDE-1 (MCP-1) MESSENGER-RNA EXPRESSION IN THE SYNOVIAL TISSUE OF RABBITS WITH ANTIGEN ARTHRITIS AND IN CULTURED SYNOVIAL-CELLS

Since IL-8 and MCP-1 are chemoattractant proteins that participate in the recruitment of inflammatory cells into the arthritic joint, we exa mined the effects of tenidap, a new anti-inflammatory drug of the oxin dole family, on IL-8 and MCP-1 expression in the joints of rabbits wit h acute antigen arthritis. The model was induced by injecting 5 mg/ml ovalbumin into the knees of 20 preimmunized rabbits. Animals were rand omized into two groups: treated with tenidap (15 mg/kg per 12 h), or u ntreated. The effect of tenidap treatment was evaluated on chemokine p roduction in synovial membranes of rabbits with arthritis and in cultu red monocytic and synovial cells (SC). By immunoperoxidase staining, c hemokines were localized in the synovial tissue. Chemokine messenger R NA levels in the synovial membranes and in cultured cells were analyse d by reverse transcription-polymerase chain reaction (RT-PCR). At the end of the study, tenidap significantly reduced neutrophil infiltratio n into the joint cavity (27 +/- 4 x 10(6) cells/ml versus 45 +/- 6 x 1 0(6) cells/ml in untreated; P < 0.05), and synovial effusion (134 +/- 15 mu l versus 236 +/- 19 mu l in untreated; P < 0.005). Untreated rab bits showed synovial membrane up-regulation in mRNA expression of IL-8 and MCP-1 (11- and seven-fold versus healthy rabbits, respectively) t hat was markedly decreased by tenidap (two- and three-fold versus heal thy rabbits, respectively). IL-8 and MCP-1 were localized in the synov ial tissue in a perivascular pattern and areas of the interstitium and lining, mostly coinciding with cell infiltration. Tenidap also reduce d the accumulation of IL-8 and MCP-1 proteins. In cultured synovial an d monocytic cells, tumour necrosis factor-alpha (TNF-alpha) elicited a n increase in gene expression of IL-8 (four- and nine-fold, respective ly) and MCP-1 (nine- and four-fold, respectively) that was significant ly reversed in both cell types by 10 mu M tenidap. These results sugge st that the beneficial effect of tenidap in acute antigen arthritis co uld be related to the downregulation in gene expression and synthesis of IL-8 and MCP-1, two key chemokines involved in the recruitment of i nflammatory cells.