title: P2X7 receptor modulation of beta-amyloid- and LPS-induced cytokine secretion from human macrophages and microglia.
abstract: To test whether extracellular ATP can play a role in the neuroimmunopathology of Alzheimer's disease (AD), we evaluated the capacity of the ATP-binding purinoreceptor, P2X7, to modulate cytokine secretion on cultured human macrophages and microglia pre-activated 24 h with the 42 amino acid beta-amyloid peptide (Abeta(1-42)) or lipopolysaccharide. Thirty minutes of exposure to the selective P2X7 agonist 2'-3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP) resulted in the secretion of IL-1beta after either Abeta(1-42) or LPS stimulation of human macrophages that was dependent on the concentration of the stimulus used to pre-activate the cells. Further tests on human microglia treated with BzATP (300 microM) resulted in a 1.5- and 3.5-fold enhancement of IL-1alpha and IL-1beta secretion, respectively, from cells pre-activated by 10 microM Abeta(1-42) and a 1.6- and 3.9-fold enhancement of IL-1alpha and IL-1beta secretion, respectively, from cells pre-activated by 1 microg/ml LPS. BzATP induction of IL-1alpha and IL-1beta secretion from microglia was completely reversed by pre-incubation of the cells with the P2X7 antagonist, adenosine 5'-triphosphate 2',3'-acyclic dialcohol (oxidized ATP). In contrast to its effects on IL-1alpha and IL-1beta secretion, BzATP induced TNF-alpha after LPS stimulation, but not after stimulation with Abeta(1-42), induced IL-18 secretion regardless of whether microglia were pre-activated and attenuated IL-6 secretion after either LPS or Abeta(1-42) pre-activation. These results demonstrate that extracellular ATP can modulate Abeta-induced cytokine secretion from human macrophages and microglia and thus may play a role in the neuroimmunopathology of AD.
authors.affiliation: Department of Safety Pharmacology, Aventis Pharmaceuticals, Inc., Bridgewater, NJ 08807-0800, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rampe
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Garth E
authors.initials: GE
authors.lastname: Ringheim
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D008070:Lipopolysaccharides; C546468:P2RX7 protein, human; D010446:Peptide Fragments; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C075222:amyloid beta-protein (1-42); C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; C017199:2',3'-dialdehyde ATP; D000255:Adenosine Triphosphate