Selective inhibition of interleukin-8-induced neutrophil chemotaxis by ketoprofen isomers

Cinzia Bizzarri, Sabrina Pagliei, Laura Brandolini, Patrizia Mascagni, Gianfranco Caselli, Pietro Transidico, Silvano Sozzani, Riccardo Bertini

Research output: Contribution to journalArticle

Abstract

Although it is commonly accepted that the anti-inflammatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is mainly associated to their ability to inhibit the cyclooxygenase (COX) enzyme system, several results indicate that non-COX mechanisms could be important in the therapeutical effect of these drugs. The aim of this study was to define if NSAIDs could exert, at least in part, their anti-inflammatory effect by inhibiting the activities of human polymorphonuclear leukocytes (PMNs) triggered by chemotactic stimuli and, if so, to understand the relationship of this effect with COX inhibition. A unique opportunity to dissociate the inhibition of prostaglandin (PG) synthesis from other therapeutical properties of NSAIDs is constituted by ketoprofen isomers being the S-isomer 100 time more potent than R-isomer on COX inhibition. Our results show that R- and S-ketoprofen, independently of their potency as PG inhibitors, proved very efficacious in selective inhibition of interleukin-8 (IL-8) chemotaxis. Inhibition of IL-8 chemotaxis was not restricted to ketoprofen isomer as it could be observed also with drugs belonging to different classes of NSAIDs and it was obtained at drug concentration superimposable to plasma levels after therapeutic administration in patients. Reduction of IL-8 migration by ketoprofen isomers was paralleled by selective inhibition of PMN response in terms of intracellular calcium concentration ([Ca2+]i) increase and extracellular signal regulated kinase(ERK)-2 activation, two intracellular mediators reported to be critical for PMN activities. It is concluded that inhibition of IL-8 chemotaxis could represent a new clinical target for ketoprofen isomers and, in fact, contribute to the anti-inflammatory activity of NSAIDs.

Original languageEnglish
Pages (from-to)1429-1437
Number of pages9
JournalBiochemical Pharmacology
Volume61
Issue number11
DOIs
Publication statusPublished - Jun 1 2001

Keywords

  • Chemotaxis
  • Interleukin-8
  • Intracellular mediators
  • Isomers
  • Ketoprofen
  • Neutrophils

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Bizzarri, C., Pagliei, S., Brandolini, L., Mascagni, P., Caselli, G., Transidico, P., Sozzani, S., & Bertini, R. (2001). Selective inhibition of interleukin-8-induced neutrophil chemotaxis by ketoprofen isomers. Biochemical Pharmacology, 61(11), 1429-1437. https://doi.org/10.1016/S0006-2952(01)00610-4