P2X7 receptor modulation of β-amyloid- and LPS-induced cytokine secretion from human macrophages and microglia

• Published in: Journal of neuroimmunology Vol. 147; no. 1; pp. 56 - 61
• Main Authors: Rampe, David, Wang, Lin, Ringheim, Garth E.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2004
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - pharmacology; Alzheimer's disease; Amyloid beta-Peptides - pharmacology; Analysis of Variance; Cells, Cultured; Cytokines - metabolism; Dose-Response Relationship, Drug; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Microglia; Microglia - drug effects; Microglia - metabolism; P2X7; Peptide Fragments - pharmacology; Purinergic P2 Receptor Agonists; Receptors, Purinergic P2 - metabolism; Receptors, Purinergic P2X7; β-Amyloid; β-Amyloid; Inflammation; P2X7; Macrophages; Alzheimer's disease; Microglia
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/j.jneuroim.2003.10.014

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 β-amyloid peptide (Aβ(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-1β after either Aβ(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 μM) resulted in a 1.5- and 3.5-fold enhancement of IL-1α and IL-1β secretion, respectively, from cells pre-activated by 10 μM Aβ(1–42) and a 1.6- and 3.9-fold enhancement of IL-1α and IL-1β secretion, respectively, from cells pre-activated by 1 μg/ml LPS. BzATP induction of IL-1α and IL-1β 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-1α and IL-1β secretion, BzATP induced TNF-α after LPS stimulation, but not after stimulation with Aβ(1–42), induced IL-18 secretion regardless of whether microglia were pre-activated and attenuated IL-6 secretion after either LPS or Aβ(1–42) pre-activation. These results demonstrate that extracellular ATP can modulate Aβ-induced cytokine secretion from human macrophages and microglia and thus may play a role in the neuroimmunopathology of AD.