In vivo B1 kinin-receptor upregulation.: Evidence for involvement of protein kinases and nuclear factor κB pathways

1 Intradermal (i.d.) injection of cytokines, IL-1 beta and TNF alpha (5 ng, 60 and 30 min prior) produces a rapid onset up-regulation of des-Arg(9)-BK-mediated rat paw oedema. Here we analyse the mechanisms involved in des-Arg(9)-BK-induced oedema in animals pre-treated with IL-1 beta or TNF alpha. 2 Co-injection of anti-IL-1 beta, anti-TNF alpha and anti-IL-8 (50 ng) significantly inhibited des-Arg(9)-BK-induced oedema in animals pre-treated with IL-1 beta (65, 37 and 42%) or TNF alpha (39, 64, 25%). IL-1 receptor antagonist (IRA, 100 mu g) or IL-10 (10 ng) inhibited the oedema caused by des-Arg(9)-BK, in rats that had received either IL-1 beta (67 and 63%) or TNF alpha (46 and 35%). 3 Co-injection of the PKC inhibitors, staurosporine (10 nmol) or RO 318220 (30 nmol) inhibited des-Arg(9)-BK-induced paw oedema (44 and 42% for IL-1 beta and, 53 and 30% for TNF alpha, respectively). Genistein (tyrosine kinase inhibitor, 2.5 mg kg(-1) s.c.) or PD 098059 (MAP-kinase inhibitor, 30 nmol) produced marked inhibition of des-Arg(9)-BK-induced oedema (58 and 39% for IL-1 beta and 31 and 35% for TNF alpha respectively). 4 The NF-kappa B inhibitors TLCK (2 mg kg(-1), i.p.) and PDCT (100 mg kg(-1), i.p.) significantly inhibited the oedema of des-Arg(9)-BK in IL-1 beta (27 and 83%) or TNF alpha (28 and 80%) pre-treated animals. 5 It is concluded that up-regulation of B-1 receptors modulated by IL-1 beta or TNF alpha involves the release of other cytokines, activation of PKC and tyrosine kinase pathways, co-ordinated with the activation of MAP-kinase and nuclear factor kappa B, reinforcing the view that B-1 receptors may exert a pivotal role in modulating chronic inflammatory processes.