Tenidap decreases IL-8 and monocyte chemotactic peptide-1 (MCP-1) mRNA expression in the synovial tissue of rabbits with antigen arthritis and in cultured synovial cells

Abstract

Since IL-8 and MCP-1 are chemoattractant proteins that participate in the recruitment of inflammatory cells into the arthritic joint, we examined the effects of tenidap, a new anti-inflammatory drug of the oxindole family, on IL-8 and MCP-1 expression in the joints of rabbits with acute antigen arthritis. The model was induced by injecting 5 mg/ml ovalbumin into the knees of 20 preimmunized rabbits. Animals were randomized into two groups: treated with tenidap (15 mg/kg per 12 h), or untreated. The effect of tenidap treatment was evaluated on chemokine production in synovial membranes of rabbits with arthritis and in cultured monocytic and synovial cells (SC). By immunoperoxidase staining, chemokines were localized in the synovial tissue. Chemokine messenger RNA levels in the synovial membranes and in cultured cells were analysed by reverse transcription-polymerase chain reaction (RT-PCR). At the end of the study, tenidap significantly reduced neutrophil infiltration into the joint cavity (27+/-4 x 10(6) cells/ml versus 45+/-6 x 10(6) cells/ml in untreated; P<0.05), and synovial effusion (134+/-15 microl versus 236+/-19 microl in untreated; P<0.005). Untreated rabbits showed synovial membrane up-regulation in mRNA expression of IL-8 and MCP-1 (11- and seven-fold versus healthy rabbits, respectively) that was markedly decreased by tenidap (two- and three-fold versus healthy rabbits, respectively). IL-8 and MCP-1 were localized in the synovial tissue in a perivascular pattern and areas of the interstitium and lining, mostly coinciding with cell infiltration. Tenidap also reduced the accumulation of IL-8 and MCP-1 proteins. In cultured synovial and monocytic cells, tumour necrosis factor-alpha (TNF-alpha) elicited an increase in gene expression of IL-8 (four- and nine-fold, respectively) and MCP-1 (nine- and four-fold, respectively) that was significantly reversed in both cell types by 10 microM tenidap. These results suggest that the beneficial effect of tenidap in acute antigen arthritis could be related to the down-regulation in gene expression and synthesis of IL-8 and MCP-1, two key chemokines involved in the recruitment of inflammatory cells.

A Potent and Selective Nonpeptide Antagonist of CXCR2 Inhibits Acute and Chronic Models of Arthritis in the Rabbit

“…In the LPS-and OVA-induced arthritis models, it is likely that the CXCR2 antagonist reduced synovial fluid leukocyte numbers by a similar mechanism, with the initial inflammatory stimulus (LPS or Ag) inducing the production of rabbit ELR ϩ chemokines, the chemotactic activities of which are inhibited by the antagonist. In the present study, as well as in those of other investigators (29,49), production of synovial fluid IL-8 was induced following LPS or Ag injection, consistent with this hypothesis.…”

Functional IL-2 Receptor β (CD122) and γ (CD132) Chains Are Expressed by Fibroblast-Like Synoviocytes: Activation by IL-2 Stimulates Monocyte Chemoattractant Protein-1 Production

“…Addition of neutralizing mAb to CD122 caused specific inhibition of IL-2-stimulated MCP-1 production, demonstrated by the decrease in MCP-1 produced following IL-2, but not IL-1␤, stimulation in the presence of anti-CD122. situation may be further complicated by the possibility that the types of chemokines produced may be dictated by the combination of cytokines produced locally, because many cytokines have the ability to regulate the MCP-1 gene (20,34). Thus, in lung fibroblast cultures IFN-␥ synergized with TNF-␣ to produce RANTES, while IL-4 synergized with TNF-␣ to produce eotaxin (35).…”

Chronic arthritis aggravates vascular lesions in rabbits with atherosclerosis: A novel model of atherosclerosis associated with chronic inflammation

“…Two weeks after starting the diet, an endothelial lesion was induced in both femoral arteries by the intravascular instillation of gaseous nitrogen under general anesthesia (26)(27)(28)(29). AIA was induced as previously described, with some modifications that were intended to produce a severe phenotype (20,(30)(31)(32). Briefly, animals were given 2 intradermal injections of 1 ml ovalbumin (OVA) (4 mg/ml; Sigma, St. Louis, MO) in Freund's complete adjuvant (Difco, Detroit, MI), 14 days apart, beginning the same week as the hyperlipemic diet ( Figure 1A).…”

“…Moreover, the progression of RA is driven by proinflammatory cytokines, chemokines, and adipokines, as well as different T cell-dependent mediators that have also been associated with the appearance of plaque-related complications (12,(15)(16)(17)(18). The activation of chemokines and the expression of a variety of surface adhesion molecules promote leukocyte trafficking toward the site of inflammation, as demonstrated in experimental arthritis, both in situ and in peripheral blood (19,20). In particular, monocyte chemoattractant protein 1 (CCL2) mediates the migration of mononuclear cells to the inflamed joints, and its induction could explain the persistent activation of these cells that are involved in joint destruction.…”