Suppressive effect of selective cyclooxygenase-2 inhibitor on cytokine release in human neutrophils

Int Immunopharmacol. 2003 Oct;3(10-11):1519-28. doi: 10.1016/S1567-5769(03)00179-6.

Abstract

To clarify whether a selective cyclooxygenase-2 (COX-2) inhibitor can affect various functions in human peripheral blood neutrophils. For this purpose, the effects of selective COX-2 inhibitors, NS-398 and nimesulide, on the expression of COX-2, PGE2 release and respiratory burst, degranulation and cytokine release in activated neutrophils were examined. Peripheral blood neutrophils were stimulated with formyl-methionyl-leucyl-phenylalanine (FMLP; 100 nM) or opsonized zymosan (OZ; 200 microg/ml). Then, the expression of COX-2 at protein and mRNA levels was detected by Western blot analysis and RT-PCR. The concentration of prostaglandin E2 (PGE2) and cytokines in the culture supernatant of neutrophils was determined using ELISA. Superoxide generation was measured by the cytochrome c reduction method. Elastase activity was measured using a chromogenic substrate assay specific for human neutrophil elastase. FMLP and OZ enhanced PGE2 release through induction of COX-2 protein and mRNA expression. FMLP- or OZ-induced PGE2 release was abolished by the addition of NS-398 or nimesulide; nevertheless, even a high concentration of COX-2 inhibitor did not change FMLP- or OZ-induced expression of COX-2 at message and protein levels. Although FMLP- or OZ-induced superoxide generation and elastase release were not affected by the addition of COX-2 inhibitor, cytokine release such as interleukin (IL)-1beta, IL-6 and IL-8 was significantly inhibited by high concentration of COX-2 inhibitor, but tumor necrosis factor-alpha (TNF-alpha) was partially attenuated. These studies showed that selective COX-2 inhibitors, NS-398 and nimesulide, suppressed PGE2 and proinflammatory cytokine release in activated neutrophils. These results suggest that selective COX-2 inhibitors may contribute to resolution of acute inflammation through the reduction of inflammatory cytokine release in activated neutrophils.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cells, Cultured
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • Cytokines / antagonists & inhibitors*
  • Dinoprostone / antagonists & inhibitors
  • Dose-Response Relationship, Drug
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / biosynthesis
  • Membrane Proteins
  • Neutrophils* / enzymology
  • Neutrophils* / metabolism
  • Nitrobenzenes / pharmacology
  • Prostaglandin-Endoperoxide Synthases / biosynthesis
  • Sulfonamides / pharmacology
  • Superoxides / antagonists & inhibitors

Substances

  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Cytokines
  • Isoenzymes
  • Membrane Proteins
  • Nitrobenzenes
  • Sulfonamides
  • Superoxides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone
  • nimesulide