Selective inhibition of interleukin-8-induced neutrophil chemotaxis by ketoprofen isomers 11Abbreviations: NSAIDs, non-steroidal anti-inflammatorydrugs; COX, cyclooxygenase; PG, prostaglandin; PMN, humanpolymorphonuclear leukocyte; IL-8, interleukin-8;[Ca2+]i, intracellular calcium concentration;MAPK, mitogen-activated protein kinases; fMLP,N-formyl-methionyl-leucyl-phenylalanine; ERK, extracellular signalregulated kinase; C5a, fifth component of complement; MCP-1, monocytechemotactic protein-1; NAP-2, neutrophil activating protein-2; GCP-2,granulocyte chemotactic peptide-2; PVP, polyvinylpyrrolidone; HBSS,Hank’s balanced salt solution; ENA-78, epithelial-derived neutrophilactivating protein-78; ECL, enhanced chemiluminescent; FURA-2AM;1-[2-(5-carboxyoxazol-2-yl)-6-amino-benzofuran-5-oxy]-2-(2′-amino-5′-ethlphenoxy)-ethane-N,N,N′,N′-tetraaceticacid pentaacetoxy methylester; MGSA/GRO, melanoma growth stimulatoryactivity/gene product of gro gene

Autor: Pietro Transidico, Patrizia Mascagni, Cinzia Bizzarri, Riccardo Bertini, Gianfranco Caselli, Silvano Sozzani, Laura Brandolini, Sabrina Pagliei
Rok vydání: 2001
Předmět:
Zdroj: Biochemical Pharmacology. 61:1429-1437
ISSN: 0006-2952
DOI: 10.1016/s0006-2952(01)00610-4
Popis: 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 ([Ca 2+ ] 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.
Databáze: OpenAIRE
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