Novel effects mediated by bradykinin and pharmacological characterization of bradykinin B<sub>2</sub> receptor antagonism in human synovial fibroblasts

Bellucci, Francesca; Cucchi, Paola; Catalani, Claudio; Giuliani, Sandro; Meini, Stefania; Maggi, C.A.

doi:10.1111/j.1476-5381.2009.00511.x

Cited by 23 publications

(29 citation statements)

References 50 publications

(101 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…B2 receptor is a G protein-coupled receptor that activates the phospholipase C (PLC) and MAPK pathways. In human synoviocytes, bradykinin stimulates IL-6 and IL-8 secretion via pathways involving the activation of PLC, p38, JNK, ERK1/2 MAPKs, and NFκB [21]; however, how bradykinin, by binding to B2 receptor, activates NFκB in human synoviocytes is unclear. Considering that NFκB is central to all TLR pathways, we speculated that alterations in TLR-2 and/or TLR-4 signaling might contribute to cytokine level changes induced by BDKRB2 +9/-9 polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

“…Non-transfected cells or siRNA-transfected cells were grown to near confluence and incubated with or without bradykinin (1 μM) for 24h in the presence or absence of the specific B2 receptor antagonist MEN16132 (1 μM, SigmaAldrich) or icatibant (1 μM, Sigma-Aldrich), or the specific p38 inhibitor SB203580 (10μM, Sigma-Aldrich), the specific JNK1/2 inhibitor SP600125 (30 μM, Sigma-Aldrich), or the specific ERK1/2 inhibitor PD98059 (30 μM, Sigma-Aldrich). The inhibitor concentrations in this study were selected according to the previous reports [21,26]. In experiments using transfected cells, cells were incubated with a final concentration of 100 nM TLR-2 siRNA or scrambled siRNA (Scr.…”

Section: Bdkrb2 Genotypingmentioning

confidence: 99%

“…BDKRB2 is present in human synovial tissues and in cultured human synoviocytes [18][19][20]. Longterm bradykinin stimulation of human synoviocytes leads to increased release of IL-6 and IL-8 [21]. Administration of a specific B2 receptor antagonist has been reported to reduce inflammatory pain in rats [22].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

Chen

Zhang

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The bradykinin B2 receptor (BDKRB2) +9/-9 gene polymorphisms have been shown to be associated with the susceptibility and severity of osteoarthritis (OA); however, the underlying mechanisms are unclear. In this study, we investigated the correlation between the BDKRB2 +9/-9 polymorphisms and pro-inflammatory cytokine levels in OA and the molecular mechanisms involved. Methods: A total of 156 patients with primary knee OA and 121 healthy controls were enrolled. The BDKRB2 +9/-9 polymorphisms were genotyped. The tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 levels were determined using Enzyme-linked immunosorbent assay (ELISA). The toll-like receptor (TLR)-2 and TLR-4 mRNA levels were determined by quantitative real-time PCR. The basal and bradykinin-stimulated pro-inflammatory cytokine secretion in human OA synoviocytes and the involvement of TLR-2 and mitogen-activated protein kinases (MAPKs) were investigated. Results: The presence of -9 bp genotype is associated with higher TNF-α, IL-6, and IL-8 levels and higher TLR-2 expression in OA patients. The basal and bradykinin-induced TLR-2 expressions in human OA synoviocytes were significantly reduced by specific inhibitors of p38, JNK1/2, and ERK1/2. Both the B2 receptor antagonist MEN16132 and TLR-2 silencing inhibited IL-6 and IL-8 secretion in human OA synoviocytes. Conclusion: The data suggested that the BDKRB2 +9/-9 polymorphisms influence pro-inflammatory cytokine levels in knee osteoarthritis by altering TLR-2 expression.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Bdkrb2 Genotypingmentioning

confidence: 99%

See 1 more Smart Citation

TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

Chen

Zhang

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…BK, also detected in the synovial fluid from patients affected by osteoarthritis (OA) or rheumatoid arthritis (RA) (Bond et al 1997;Cassim et al 2009), acts by activating B 2 receptors present both in synovial cells and endothelial lining cells of blood vessels (Cassim et al 1997). In fibroblast-like synoviocytes, BK induces release of prostaglandins, cytokines, and chemokines (Meini and Maggi 2008;Bellucci et al 2009), which are involved in inflammation of the synovium, sensitization of sensory fibers, and degradation of extracellular matrix (Goldring and Goldring 2004;Haringman et al 2004;White et al 2007), all aspects that characterize OA pathophysiology. In this view, antagonists for the kinin B 2 receptor may represent an alternative symptomatic therapy for OA.…”

Section: Introductionmentioning

confidence: 98%

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

Meini

Cucchi

Tinti

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

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 1β (IL-1β) 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 μM, 30 min preincubation). IL-1β increased PGE(2) 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(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-1β 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-1β. The prevention of this synergism by fasitibant indicates BK B(2) receptor blockade as an alternative symptomatic therapy for osteoarthritis.

show abstract

“…The administration of Bradykinin B2 receptor (BDKRB2) antagonists, which reportedly produce enduring analgesic effects in patients afflicted with OA of the knee, signifies the potential key role played by bradykinins in the progression of the disease. 9,10 Bradykinins are inflammatory mediators belonging to a family of oligopeptides that result from the enzymatic action of kallikreins proteolytically cleaving kininogens and are vasodilators known to be produced by the synovium. 11,12 These newly produced bradykinins contribute to both the initiation and maintenance of inflammation, leading to the production of pain, advancement of the highly catabolic state, subsequent chondrocyte apoptosis, and the progressive degeneration of articular cartilage.…”

Section: Introductionmentioning

confidence: 99%

BDKRB2 +9/−9 bp polymorphisms influence BDKRB2 expression levels and NO production in knee osteoarthritis

Chen

Zhang

et al. 2016

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

The bradykinin B2 receptor (BDKRB2) plays a key role in the inflammation process of osteoarthritis. Nitric oxide has also long been considered to be a catabolic factor that contributes to inflammatory response and the osteoarthritis disease pathology. Several studies have reported that the BDKRB2 þ9/À9 bp polymorphisms are associated with transcription of the receptor. However, the roles of BDKRB2 polymorphisms in inflammation in osteoarthritis remain unclear. This study enrolled 156 subjects with primary knee osteoarthritis and 58 healthy volunteers. BDKRB2 polymorphisms were genotyped, and the mRNA and protein levels of BDKRB2 in synovial tissues from osteoarthritis patients were measured by quantitative real-time polymerase chain reaction and western blot analysis, respectively. Nitric oxide production in serum from patients with osteoarthritis was measured using a nitric oxide assay kit. We found that the mean BDKRB2 mRNA levels were significantly higher in Kallgren-Lawrence grade-4 osteoarthritis patients than patients with lower grade osteoarthritis. The þ9/À9 bp polymorphisms significantly affected the BDKRB2 mRNA and protein expression levels in synovial tissues from osteoarthritis subjects. Osteoarthritis patients with þ9/À9 and À9/À9 genotypes had higher BDKRB2 expression levels in synovial tissue and nitric oxide production in serum. Moreover, positive correlation was found between the BDKRB2 levels in synovial tissue and nitric oxide production. Compared with health controls, significant increases of nitric oxide production in osteoarthritis were detected which were associated with increasing severity of osteoarthritis. Multiple linear regression analysis (adjusted for gender and age) showed serum nitric oxide level was positively associated with BDKRB2 polymorphism and Kallgren-Lawrence grade and was inversely associated with obesity. Our findings showed that the BDKRB2 þ9/À9 bp polymorphisms affected the gene expression and nitric oxide production, which were associated with radiographic severity of osteoarthritis, suggesting that the BDKRB2 þ9/À9 bp polymorphisms may act as a genetic modulator of osteoarthritis, and play an essential role in inflammatory process in osteoarthritis.

show abstract

Novel effects mediated by bradykinin and pharmacological characterization of bradykinin B₂ receptor antagonism in human synovial fibroblasts

Cited by 23 publications

References 50 publications

TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

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

BDKRB2 +9/−9 bp polymorphisms influence BDKRB2 expression levels and NO production in knee osteoarthritis

Contact Info

Product

Resources

About

Novel effects mediated by bradykinin and pharmacological characterization of bradykinin B2 receptor antagonism in human synovial fibroblasts

Cited by 23 publications

References 50 publications

TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

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

BDKRB2 +9/−9 bp polymorphisms influence BDKRB2 expression levels and NO production in knee osteoarthritis

Contact Info

Product

Resources

About

Novel effects mediated by bradykinin and pharmacological characterization of bradykinin B₂ receptor antagonism in human synovial fibroblasts