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 B-2 receptor antagonist fasitibant (MEN16132) on the proinflammatory effect of bradykinin (BK) and its interaction with interleukin 1 beta (IL-1 beta) in human synoviocytes. PGE(2) 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 PGE(2) and transient COX-2 gene expression that were prevented by pretreatment with fasitibant (1 mu M, 30 min preincubation). IL-1 beta increased PGE(2) release and COX-2 expression more than BK alone. The combined treatment of cells with BK and IL-1 beta induced an even increase of released PGE(2) and COX-2 gene and protein expression indicating a synergistic rather than an additive effect, not related to an increase of B-2 receptors density or its coupling. These potentiating effects of BK on PGE(2) production and increased COX-2 expression produced by IL-1 beta were B-2-receptor-mediated as fasitibant could prevent them. None of the treatments induced changes in the COX-1 expression. The synergistic PGE(2) 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-1 beta. The prevention of this synergism by fasitibant indicates BK B-2 receptor blockade as an alternative symptomatic therapy for osteoarthritis.