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 stimuli may play a role in the recruitment and activation of further neutrophils in an inflammatory reaction. Here, we have evaluated the sequence of early events leading to interleukin-8 production by phagocytosing neutrophils. Kinetic experiments showed that the phagocytosis of zymosan particles by human neutrophils was rapid in onset. In contrast, interleukin-8 production was more protracted and only detectable 6 h later. Nevertheless, inhibition of phagocytosis with cytochalasins B or D suppressed the late interleukin-8 production. Activation of neutrophils with zymosan failed to enhance CD11/CD18 expression on the neutrophil surface but led to an increase in the expression of an activation-dependent epitope on CD11/CD18. Pretreatment with 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), significantly blocked the increase in the expression of the activation epitope, resulting in inhibition of the phagocytosis of zymosan and interleukin-8 production. In conclusion, the activation of neutrophils with zymosan leads to the activation of PAF receptors and this is followed by activation of CD11/CD18, phagocytosis of zymosan particles and subsequent interleukin-8 release.
Au
B T
BT
Leukocyte Biology, Biomedical Science Division, Imperial College of Science, Technology and Medicine, Exhibition Road, London SW7 2AZ, UK.
Teixeira
M M
MM
Collins
P D
PD
Williams
T J
TJ
D018845:CD11 Antigens / Q000378:metabolism*; D018821:CD18 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D003572:Cytochalasins / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D000939:Epitopes / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis*; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013997:Time Factors; D015054:Zymosan / Q000493:pharmacokinetics
D018845:CD11 Antigens; D018821:CD18 Antigens; D003572:Cytochalasins; D004095:Dihydropyridines; D000939:Epitopes; D007093:Imidazoles; D016209:Interleukin-8; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C073027:modipafant; D015054:Zymosan