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This study investigates the effect of the selective and potent B receptor antagonist fasitibant (MEN16132) on the proinflammatory effect of bradykinin (BK) and its interaction with interleukin 1β (IL-1β) in human synoviocytes. PGE content was detected in the surnatants and COX-2 and COX-1 gene and protein expression determined in the cells. Radioligand binding ([ H]BK) and BK-induced inositolphosphate experiments were performed. Incubation of synoviocytes with BK induced a sustained production of PGE and transient COX-2 gene expression that were prevented by pretreatment with fasitibant (1 μM, 30 min preincubation). IL-1β increased PGE release and COX-2 expression more than BK alone. The combined treatment of cells with BK and IL-1β induced an even increase of released PGE and COX-2 gene and protein expression indicating a synergistic rather than an additive effect, not related to an increase of B receptors density or its coupling. These potentiating effects of BK on PGE production and increased COX-2 expression produced by IL-1β were B-receptor-mediated as fasitibant could prevent them. None of the treatments induced changes in the COX-1 expression. The synergistic PGE production was abolished by the specific NF-kappaB inhibitor (BAY-117085), whereas specific inhibitors for the p38 (SB203580), JNK (SP600125), and ERK1/2 (PD98059) mitogen-activated protein kinases could prevent the prostanoid release. BK can potentiate the COX-2 gene expression and consequent prostanoid production induced by IL-1β. The prevention of this synergism by fasitibant indicates BK B receptor blockade as an alternative symptomatic therapy for osteoarthritis. [ABSTRACT FROM AUTHOR]