The role of migrating leukocytes in IL-1β-induced up-regulation of kinin B1 receptors in rats

1 The present study examines the role of migrating leukocytes in the ability of IL-1beta to induce the functional up-regulation of B-1 receptors, as assessed by kinin B, agonist-induced oedema in the rat paw. 2 Pre-treatment with the PAF receptor antagonist WEB 2086 inhibited des-Arg(9)-BK-induced oedema in IL-1beta-treated paws, while the LTB4 receptor antagonist CP105696 had no effect. Des-Arg(9)-BK-induced paw oedema was also inhibited by pre-treatment with the selectin blocker fucoidin or by an anti-CD-18 monoclonal antibody. 3 I.d. injection of IL-1beta produced a 5-10-fold increase of myeloperoxidase (MPO) activity in the rat paw. The increase in MPO activity was significantly inhibited by WEB 2086 (46+/-9%), fucoidin (68+/-5%) or the CD-18 antibody (84+/-3%). In contrast, i.d. injection of TNFalpha a dose known to upregulate the B-1 receptor functionally did not induce any significant increase in MPO activity. 4 Des-Arg(9)-BK alone had no effect in MPO activity but enhanced (by about 40%) the response induced by IL-1beta, an effect prevented by the B-1 receptor antagonist des-Arg(9)-[Leu(8)]-BK. 5 The concentration of TNF-alpha was increased in the paws after i.d. injection of IL-1beta. Pretreatment with fucoidin, WEB 2086, anti-CD-18 or CP 105695, significantly reversed the local increases in TNF-a concentrations (80+/-2; 75+/-4, 73+/-3 and 40+/-2%), respectively. 6 Finally, IL-1beta induced an increase of B-1 receptor mRNA levels in the rat paw, an effect which was prevented by fucoidin treatment. 7 Taken together, these results indicate that up-regulation of B-1 receptors in the rat paw following IL-1beta seems to involve the local recruitment of neutrophils and subsequent local TNF-alpha production. The cross-talk between kinins, cytokines and leukocytes implicate B-1 receptors in chronic inflammatory diseases.