Blockade of PAF receptors controls interleukin-8 production by regulating the activation of neutrophil CD11/CD18

The production of interleukin-8 by neutrophils in response to particulate s timuli may play a role in the recruitment and activation of further neutrop hils in an inflammatory reaction. Here, we have evaluated the sequence of e arly events leading to interleukin-8 production by phagocytosing neutrophil s. Kinetic experiments showed that the phagocytosis of zymosan particles by human neutrophils was rapid in onset. In contrast, interleukin-8 productio n was more protracted and only detectable 6 h later. Nevertheless, inhibiti on of phagocytosis with cytochalasins B or D suppressed the late interleuki n-8 production. Activation of neutrophils with zymosan failed to enhance CD 11/CD18 expression on the neutrophil surface but led to an increase in the expression of an activation-dependent epitope on CD11/CD18. Pretreatment wi th the platelet-activating factor (PAF) receptor antagonist, UK-74505 (4-(2 -chlorophenyl)-1,4-dihydro-3-ethoxycarbonyl-6-methyl-2-[4-(2-methylimidazol [4,5-c]pyrid-1-yl)phenyl]-5-[N-(2-pyridyl)carbamoyl]pyridine), significantl y blocked the increase in the expression of the activation epitope, resulti ng in inhibition of the phagocytosis of zymosan and interleukin-8 productio n. In conclusion, the activation of neutrophils with zymosan leads to the a ctivation of PAF receptors and this is followed by activation of CD11/CD18, phagocytosis of zymosan particles and subsequent interleukin-8 release. (C ) 2001 Elsevier Science B.V. All rights reserved.