Intradermal (i.d.) injection of cytokines, IL-1β and TNFα (5 ng, 60 and 30 min prior) produces a rapid onset up-regulation of des-Arg9-BK-mediated rat paw oedema. Here we analyse the mechanisms involved in des-Arg9-BK-induced oedema in animals pre-treated with IL-1β or TNFα.
Co-injection of anti-IL-1β, anti-TNFα and anti-IL-8 (50 ng) significantly inhibited des-Arg9-BK-induced oedema in animals pre-treated with IL-1β (65, 37 and 42%) or TNFα (39, 64, 25%). IL-1 receptor antagonist (IRA, 100 μg) or IL-10 (10 ng) inhibited the oedema caused by des-Arg9-BK, in rats that had received either IL-1β (67 and 63%) or TNFα (46 and 35%).
Co-injection of the PKC inhibitors, staurosporine (10 nmol) or RO 318220 (30 nmol) inhibited des-Arg9-BK-induced paw oedema (44 and 42% for IL-1β and, 53 and 30% for TNFα, 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-Arg9-BK-induced oedema (58 and 39% for IL-1β and 31 and 35% for TNFα respectively).
The NF-κB inhibitors TLCK (2 mg kg−1, i.p.) and PDCT (100 mg kg−1, i.p.) significantly inhibited the oedema of des-Arg9-BK in IL-1β (27 and 83%) or TNFα (28 and 80%) pre-treated animals.
It is concluded that up-regulation of B1 receptors modulated by IL-1β or TNFα involves the release of other cytokines, activation of PKC and tyrosine kinase pathways, co-ordinated with the activation of MAP-kinase and nuclear factor κB, reinforcing the view that B1 receptors may exert a pivotal role in modulating chronic inflammatory processes.
British Journal of Pharmacology (1999) 127, 1851–1859; doi:10.1038/sj.bjp.0702715