title: Bradykinin decreases nitric oxide release from microglia via inhibition of cyclic adenosine monophosphate signaling.
abstract: Bradykinin (BK) is a major potent inflammatory mediator outside the central nervous system. In Alzheimer's disease, BK release and BK receptor expression in brain tissues are upregulated relatively early during the course of the disease. Hence, BK was believed to promote neuroinflammation. However, BK was recently reported to possess anti-inflammatory and neuroprotective roles. Exposure of BV2 microglial cell line to BK lead to a decrease in NO release from unstimulated cells as well as a dose-dependent attenuation, mediated by both B1 and B2 receptors, in lipopolysaccharide (LPS)-induced NO production. In this study we examined whether cyclic adenosine monophosphate (cAMP) signaling is involved in BK-mediated effect in microglial nitric oxide (NO) production. A protein kinase A (PKA) inhibitor mimicked the effects of BK, while cAMP elevating agents antagonized BK-mediated NO decrease. Moreover, BK inhibited the activation of cAMP responsive element binding protein (CREB). In addition, BK protected microglial cells from death triggered by combinations of LPS and each of the cAMP elevating agents. Finally, the addition of Gαi protein inhibitor abrogated the effects of BK on NO release, and the expression of Gαi protein in the plasma membrane was induced by BK. These results suggest that BK-mediated reduction in microglial NO production depends on coupling to Gi protein and also involves inhibition of cAMP-PKA-CREB signaling.
authors: Department of Clinical Pharmacology, Ben Gurion University of the Negev, P.O.B. 653, Beer-Sheva 84105, Israel. saritbe@bgu.ac.il
authors: Sarit
authors: S
authors: Ben-Shmuel
authors: Abraham
authors: A
authors: Danon
authors: Sigal
authors: S
authors: Fleisher-Berkovich
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage* / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D018002:Receptors, Bradykinin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D008070:Lipopolysaccharides; D018002:Receptors, Bradykinin; D009569:Nitric Oxide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D001920:Bradykinin