C. Bizzarri et al., Selective inhibition of interleukin-8-induced neutrophil chemotaxis by ketoprofen isomers, BIOCH PHARM, 61(11), 2001, pp. 1429-1437
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.