Cytokines and neutrophils as important mediators of platelet-activating factor-induced kinin B1 receptor expression.
PAF injection into the rat paw is accompanied by the concomitant activation of NF-kappaB and neutrophil influx, which appears to be relevant to the up-regulation of kinin B1 receptors. Herein, we analyse the role of TNF-alpha and IL-1beta production for PAF-induced B1 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 B1 receptor upregulation. In our experiments, treatment with PAF resulted in a marked increase of B1 receptor-mediated paw oedema and in situ production of TNF-alpha at 1 h and IL-1beta at 3 and 6 h later. B1 receptor-mediated paw oedema was significantly inhibited by anti-TNF-alpha antibody and by interleukin-1 receptor antagonist (IRA). TNF-alpha was necessary for the local PAF-induced IL-1beta production. NF-kappaB blocker PDTC prevented the production of both TNF-alpha and IL-1beta, indicating that cytokine production is NF-kappaB dependent. Depletion of neutrophils with an anti-PMN antibody prevented IL-1beta, but not TNF-alpha, production. Although both TNF-alpha and IL-1beta are relevant to functional B1 receptor upregulation, PAF-induced increase in B1 receptor mRNA was markedly suppressed by anti-TNF-alpha and, to a lesser extent, by IRA. B1 receptor mRNA expression was also prevented by the anti-PMN antibody. In conclusion, the activation of the TNF-alpha/neutrophil axis by PAF seems to be sufficient for B1 receptor mRNA production. However, the TNF-alpha/neutrophil axis is also necessary for IL-1beta production. These two processes might lead to the appearance of functional kinin B1 upregulation receptors in vivo after PAF treatment.
Fernandes
Elizabeth S
ES
Department of Pharmacology, CCB, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC 88049-900, Brazil.
Passos
Giselle F
GF
Campos
Maria M
MM
de Souza
Glória E P
GE
Fittipaldi
Juliana F
JF
Pesquero
Jorge L
JL
Teixeira
Mauro M
MM
Calixto
João B
JB
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology*; D004487:Edema / Q000473:pathology; D007375:Interleukin-1 / Q000096:biosynthesis; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000096:biosynthesis*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D007375:Interleukin-1; D016328:NF-kappa B; D010972:Platelet Activating Factor; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase