558 research outputs found
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
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