title: Norepinephrine differentially modulates the innate inflammatory response provoked by amyloid-β peptide via action at β-adrenoceptors and activation of cAMP/PKA pathway in human THP-1 macrophages.
abstract: Evidence indicates that norepinephrine (NE) has antiinflammatory activities and plays a neuroprotective role where inflammatory events contribute to Alzheimer's disease pathology. Here, we evaluated the effects of NE on amyloid beta 1-42 (Aβ1-42)-induced cytotoxicity and proinflammatory cytokine/chemokine secretion, and determined the mechanisms through which NE exerts its actions in human THP-1 macrophages. NE clearly reduced the Aβ1-42-mediated production of the proinflammatory chemokine, monocytic chemotactic protein-1 (MCP-1/CCL2). In contrast to its ability to reduce MCP-1 secretion, NE enhanced the amounts of the proinflammatory cytokine interleukin (IL)-1β secreted from Aβ1-42 treated cells. NE significantly reduced the Aβ1-42-induced cytotoxicity in situations where it contributed to the increased IL-1β and decreased MCP-1 during Aβ1-42 stimulation. The ability of NE to differentially modulate the Aβ1-42-induced immune responses was mediated by β-adrenoceptors, as the aforementioned effects were replicated by the β-adrenoceptor agonist, isoproterenol, and blocked by the β-adrenoceptor antagonist, dl-propranolol. Of note, the NE effects on Aβ1-42-induced responses were mimicked by dbcAMP and forskolin, but significantly blocked by H89, an inhibitor of PKA. Moreover, NE abolished Aβ1-42-mediated decline of CREB phosphorylation. Overall, NE suppresses Aβ1-42-mediated cytotoxicity and MCP-1 secretion, but enhances Aβ-mediated IL-1β secretion through action at β-adrenoceptors, accompanied by activation of cAMP/PKA pathway and CREB in human microglia-like THP-1 cells.
authors.affiliation: Department of Microbiology, School of Medicine, Division of Molecular Biology and Neuroscience, Ewha Medical Research Institute, Ewha Womans University Seoul, Republic of Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Yang
authors.forename: Eun Ok
authors.initials: EO
authors.lastname: Lee
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Yoo-Hun
authors.initials: YH
authors.lastname: Suh
authors.forename: Young Hae
authors.initials: YH
authors.lastname: Chong
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D002460:Cell Line; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity*; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000633:toxicity; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D018836:Inflammation Mediators; D010446:Peptide Fragments; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine