title: Inhibitory role of kinins on microglial nitric oxide and tumor necrosis factor-α production.
abstract: Brain inflammation is sustained by chronic activation of microglia and the over-production of pro-inflammatory cytokines and nitric oxide (NO), which in turn can be highly neurotoxic. Microglial activation can be regulated by neuropeptides such as bradykinin (BK) and other members of the kinin family. Kinins are well known inflammatory regulators outside the CNS. Although the kinin system is well distributed throughout the brain, the precise role of BK in the CNS is not yet clear. The aim of this study was to examine and characterize the effects of BK and related kinins on the production of NO and TNF-α in microglia. We found that BK and selective agonists for both B1 and B2 receptors, attenuated both NO and TNF-α levels in the media of BV2 microglial cells that had been stimulated with LPS. The effects of BK that were observed in BV2 cells were confirmed in primary neonatal rat microglial cells as well. In addition, all kinin agonists reduced the expression of iNOS and TNF-α protein and mRNA levels in LPS-stimulated BV2 cells. Also, while LPS activated the nuclear factor-κB (NF-κB) pathway, BK inhibited NF-κB activation by preventing degradation of the κB protein (IκB) inhibitor, abolishing translocation of p65 and p50 subunits to the nucleus and inhibiting NF-κB transcription activity. These results suggest a role for bradykinin in modulation of glial inflammation, as evidenced by attenuation of NO and TNF-α synthesis pathways in activated microglial cells.
authors.affiliation: Department of Clinical Pharmacology, Ben Gurion University of the Negev, Beer-Sheva, Israel. saritbe@bgu.ac.il
authors.forename: Ben-Shmuel
authors.initials: BS
authors.lastname: Sarit
authors.forename: Gera
authors.initials: G
authors.lastname: Lajos
authors.forename: Danon
authors.initials: D
authors.lastname: Abraham
authors.forename: Apte
authors.initials: A
authors.lastname: Ron
authors.forename: Fleisher-Berkovich
authors.initials: FB
authors.lastname: Sigal
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000819:agonists / Q000378:metabolism*; D002460:Cell Line; D004660:Encephalitis / Q000378:metabolism / Q000473:pathology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007705:Kinins / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D007705:Kinins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051550:I-kappa B Kinase; D001920:Bradykinin