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      Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis.

      The Journal of clinical investigation

      Animals, Arthritis, Experimental, immunology, physiopathology, Base Sequence, Cyclooxygenase Inhibitors, pharmacology, DNA Primers, Dexamethasone, Dinoprostone, biosynthesis, Gene Expression, drug effects, Gene Expression Regulation, Enzymologic, Indomethacin, Inflammation, prevention & control, Interleukin-6, Isoenzymes, Joints, pathology, Male, Molecular Sequence Data, Polymerase Chain Reaction, Prostaglandin-Endoperoxide Synthases, Pyrazoles, therapeutic use, RNA, Messenger, Rats, Rats, Inbred Lew, Time Factors, Tumor Necrosis Factor-alpha

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          Abstract

          Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in rat adjuvant arthritis was evaluated by characterization of COX-2 expression in normal and arthritic paws and by pharmacological inhibition of COX-2 activity. The injection of adjuvant induced a marked edema of the hind footpads with coincident local production of PGE2. PG production was associated with upregulation of COX-2 mRNA and protein in the affected paws. In contrast, the level of COX-1 mRNA was unaffected by adjuvant injection. TNF-alpha and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly reversed paw edema and reduced the level of PGE2 in paw tissue to baseline. Interestingly, treatment with the COX-2 inhibitor also reduced the expression of COX-2 mRNA and protein in the paw. Serum IL-6 and paw IL-6 mRNA levels were also reduced to near normal levels by SC-58125. Furthermore, inhibition of COX-2 resulted in a reduction of the inflammatory cell infiltrate and decreased inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125 were indistinguishable from the effects observed for indomethacin. These results suggest that COX-2 plays a prominent role in the inflammation associated with adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6 expression at inflammatory sites.

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          Author and article information

          Journal
          8647962
          507355
          10.1172/JCI118717

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