Cytokines and neutrophils as important mediators of platelet-activating factor-induced kinin B 1 receptor expression

Abstract

PAF injection into the rat paw is accompanied by the concomitant activation of NF-κB and neutrophil influx, which appears to be relevant to the up-regulation of kinin BI receptors. Herein, we analyse the role of TNF-α and IL-1β production for PAF-induced B 1 receptor upregulation in the rat paw. Additionally, we evaluate how cytokine production and neutrophil migration fit into the temporal sequence of events leading to PAF-induced B 1 receptor upregulation. In our experiments, treatment with PAF resulted in a marked increase of B 1 receptor-mediated paw oedema and in situ production of TNF-α at 1 h and IL-1β at 3 and 6 h later. B 1 receptor-mediated paw oedema was significantly inhibited by anti-TNF-α antibody and by interleukin-1 receptor antagonist (IRA). TNF-α was necessary for the local PAF-induced IL-1β production. NF-κB blocker PDTC prevented the production of both TNF-α and IL-1β, indicating that cytokine production is NF-κB dependent. Depletion of neutrophils with an anti-PMN antibody prevented IL-1β, but not TNF-α, production. Although both TNF-α and IL-1β are relevant to functional B 1 receptor upregulation, PAF-induced increase in B 1 receptor mRNA was markedly suppressed by anti-TNF-α and, to a lesser extent, by IRA. B 1 receptor mRNA expression was also prevented by the anti-PMN antibody. In conclusion, the activation of the TNF-α/neutrophil axis by PAF seems to be sufficient for B 1 receptor mRNA production. However, the TNF-α/neutrophil axis is also necessary for IL-1β production. These two processes might lead to the appearance of functional kinin B 1 upregulation receptors in vivo after PAF treatment. © 2005 Nature Publishing Group All rights reserved.