Fasitibant prevents the bradykinin and interleukin 1β synergism on prostaglandin E2 release and cyclooxygenase 2 expression in human fibroblast-like synoviocytes

This study investigates the effect of the selective and potent B2 receptor antagonist fasitibant (MEN16132) on the proinflammatory effect of bradykinin (BK) and its interaction with interleukin 1β (IL-1β) in human synoviocytes. PGE2 content was detected in the surnatants and COX-2 and COX-1 gene and protein expression determined in the cells. Radioligand binding ([3 H]BK) and BK-induced inositolphosphate experiments were performed. Incubation of synoviocytes with BK induced a sustained production of PGE2 and transient COX-2 gene expression that were prevented by pretreatment with fasitibant (1 μM, 30 min preincubation). IL-1β increased PGE2 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 PGE2 and COX-2 gene and protein expression indicating a synergistic rather than an additive effect, not related to an increase of B2 receptors density or its coupling. These potentiating effects of BK on PGE2 production and increased COX-2 expression produced by IL-1β were B2-receptor-mediated as fasitibant could prevent them. None of the treatments induced changes in the COX-1 expression. The synergistic PGE2 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 B2 receptor blockade as an alternative symptomatic therapy for osteoarthritis.