In vivo B 1 kinin‐receptor upregulation. Evidence for involvement of protein kinases and nuclear factor κB pathways

• Published in: British journal of pharmacology Vol. 127; no. 8; pp. 1851 - 1859
• Main Authors: Campos, Maria M, Souza, Glória E P, Calixto, João B
• Format: Journal Article
• Language: English
• Published: 29.01.2009
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0702715

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‐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‐1β or TNFα. Co‐injection of anti‐IL‐1β, anti‐TNFα and anti‐IL‐8 (50 ng) significantly inhibited des‐Arg 9 ‐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‐Arg 9 ‐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‐Arg 9 ‐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‐Arg 9 ‐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‐Arg 9 ‐BK in IL‐1β (27 and 83%) or TNFα (28 and 80%) pre‐treated animals. It is concluded that up‐regulation of B 1 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 B 1 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