Cytokine Reduction in the Treatment of Joint Conditions

The destruction of joints caused by rheumatoid arthritis and osteoarthritis is characterized by an imbalance of enzyme catalysed cartilage breakdown and regeneration. A complex cytokine network perpetuates joint conditions by direct regulation of metalloproteases, by indirect recruitment of cells that secrete degradative enzymes, and by inhibition of reparative processes. The destructive action of cytokines such as interleukin-1, interleukin-6 and tumour necrosis factor-α can be modulated at multiple points associated either with cytokine production or with cytokine action. Potential agents for cytokine reduction include selective anti-cytokine antibodies, anticytokine receptor antibodies, cytokine receptor antagonist proteins, and soluble and chimeric cytokine receptor molecules. Pharmacologic regulation of IL-1 and TNFα remain primary targets for treatment of arthritis, and results of early clinical trials are promising. However, the results of long-term clinical trials will be required to support the value of anti-cytokine therapy in treatment of arthritis

Nimesulide reduces interleukin-1β-induced cyclooxygenase-2 gene expression in human synovial fibroblasts

AbstractObjective To characterize the effects of nimesulide (NIM) on basal and induced cyclo-oxygenase-2 (COX-2) gene expression in human synovial fibroblasts (HSF) and to define the intracellular mechanisms that mediate the changes in COX-2 expression and synthesis in response to the drug.Design HSF were incubated with NIM and NS-398 (0, 0.03, 0.3, 3μg/ml) in the absence or presence of the COX-2 inducers interleukin-1β (IL-1β) or endotoxin (LPS). Treated cells were analysed for COX-2 mRNA and protein by Northern and Western blotting analysis, respectively. Putative transcriptional, post-transcriptional, and signaling effects of NIM on basal and induced-COX-2 expression were investigated by human COX-2 promoter studies, calcium studies, reactive oxygen species (ROS) evaluations, electrophoretic mobility shift analysis (EMSA) and half-life studies of COX-2 mRNA.Results NIM inhibited IL-1β-induced COX-2 expression and protein at sub and therapeutic concentrations (0.03–0.3μg/ml) while the non-specific NSAID, naproxen, did not. Both drugs suppressed PGE2 release by about 95%. NIM had no effect on (1) IL-1β-induced increases in NF-κB or c/EBP signaling, or (2) human COX-2 promoter activity. Stability of induced COX-2 mRNA was unaffected by NIM treatments. Pre-treatment of cells with O2radical scavengers (e.g. PDTC) or with Ca++channel blockers (e.g. verapamil) had a modest effect on IL-1β-induced COX-2 expression. NIM blocked ionomycin+thapsigargin and H2O2-induced increases in COX-2 protein synthesis.Conclusion NIM inhibits cytokine-induced COX-2 expression and protein at sub and therapeutic concentrations. At least part of this activity may be the result of NIM inhibition of calcium and/or free radical generation induced by cytokines