title: Neuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microglia.
abstract: Bradykinin (BK) has been reported to be a mediator of brain damage in acute insults. Receptors for BK have been identified on microglia, the pathologic sensors of the brain. Here, we report that BK attenuated lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta from microglial cells, thus acting as an anti-inflammatory mediator in the brain. This effect was mimicked by raising intracellular cAMP or stimulating the prostanoid receptors EP2 and EP4, while it was abolished by a cAMP antagonist, a prostanoid receptor antagonist, or by an inhibitor of the inducible cyclooxygenase (cyclooxygenase-2). BK also enhanced formation of prostaglandin E(2) and expression of microsomal prostaglandin E synthase. Expression of BK receptors and EP2/EP4 receptors were also enhanced. Using physiological techniques, we identified functional BK receptors not only in culture, but also in microglia from acute brain slices. BK reduced LPS-induced neuronal death in neuron-microglia co-cultures. This was probably mediated via microglia as it did not affect TNF-alpha-induced neuronal death in pure neuronal cultures. Our data imply that BK has anti-inflammatory and neuroprotective effects in the central nervous system by modulating microglial function.
authors.affiliation: Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Noda
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Kariura
authors.forename: Ulrike
authors.initials: U
authors.lastname: Pannasch
authors.forename: Kaori
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Seike
authors.forename: Masataka
authors.initials: M
authors.lastname: Ifuku
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kosai
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Christiane
authors.initials: C
authors.lastname: Nolte
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Aoki
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
mesh_terms: D000527:Alprostadil / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D001920:Bradykinin / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D019610:Cytoprotection / Q000276:immunology*; D004660:Encephalitis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D005911:Gliosis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D009410:Nerve Degeneration / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D018002:Receptors, Bradykinin / Q000187:drug effects / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C545651:Ptger4 protein, mouse; D018002:Receptors, Bradykinin; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D000527:Alprostadil; D001920:Bradykinin