title: TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  The data suggested that the BDKRB2 +9/-9 polymorphisms influence pro-inflammatory cytokine levels in knee osteoarthritis by altering TLR-2 expression.
authors.forename: Shuo
authors.initials: S
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Ruonan
authors.initials: R
authors.lastname: Xu
authors.forename: Yunfan
authors.initials: Y
authors.lastname: Ti
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Liwu
authors.initials: L
authors.lastname: Zhou
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000368:Aged; D001920:Bradykinin / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D043782:Receptor, Bradykinin B2 / Q000235:genetics*; D000070918:Synoviocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics*
chemical_list: D016207:Cytokines; D043782:Receptor, Bradykinin B2; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D001920:Bradykinin