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

Citation
C. Bizzarri et al., Selective inhibition of interleukin-8-induced neutrophil chemotaxis by ketoprofen isomers, BIOCH PHARM, 61(11), 2001, pp. 1429-1437
Citations number
52
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
00062952 → ACNP
Volume
61
Issue
11
Year of publication
2001
Pages
1429 - 1437
Database
ISI
SICI code
0006-2952(20010601)61:11<1429:SIOINC>2.0.ZU;2-J
Abstract
Although it is commonly accepted that the anti-inflammatory effect of nonst eroidal anti-inflammatory drugs (NSAIDs) is mainly associated to their abil ity to inhibit the cyclooxygenase (COX) enzyme system, several results indi cate 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 activit ies of human polymorphonuclear leukocytes (PMNs) triggered by chemotactic s timuli and, if so, to understand the relationship of this effect with COX i nhibition. A unique opportunity to dissociate the inhibition of prostagland in (PG) synthesis from other therapeutical properties of NSAIDs is constitu ted by ketoprofen isomers being the S-isomer 100 time more potent than R-is omer on COX inhibition. Our results show that R- and S-ketoprofen, independ ently of their potency as PG inhibitors, proved very efficacious in selecti ve inhibition of interleukin-8 (IL-8) chemotaxis. Inhibition of IL-8 chemot axis was not restricted to ketoprofen isomer as it could be observed also w ith drugs belonging to different classes of NSAIDs and it was obtained at d rug concentration superimposable to plasma levels after therapeutic adminis tration in patients. Reduction of IL-8 migration by ketoprofen isomers was paralleled by selective inhibition of PMN response in terms of intracellula r calcium concentration ([Ca2(+)](i)) increase and extracellular signal reg ulated kinase (ERK)-2 activation, two intracellular mediators reported to b e critical for PMN activities. It is concluded that inhibition of IL-8 chem otaxis could represent a new clinical target fur ketoprofen isomers and, in fact, contribute to the anti-inflammatory activity of NSAIDs. (C) 2001 Els evier Science Inc. All rights reserved.