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Differential Regulation of ATP- and UTP-Evoked Prostaglandin E2 and IL-6 Production from Human Airway Epithelial Cells.
Kountz, Timothy S; Jairaman, Amit; Kountz, Candace D; Stauderman, Kenneth A; Schleimer, Robert P; Prakriya, Murali.
  • Kountz TS; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.
  • Jairaman A; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.
  • Kountz CD; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.
  • Stauderman KA; CalciMedica, Inc., La Jolla, CA; and.
  • Schleimer RP; Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
  • Prakriya M; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL; m-prakriya@northwestern.edu.
J Immunol ; 207(5): 1275-1287, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1771322
ABSTRACT
The airway epithelial cells (AECs) lining the conducting passageways of the lung secrete a variety of immunomodulatory factors. Among these, PGE2 limits lung inflammation and promotes bronchodilation. By contrast, IL-6 drives intense airway inflammation, remodeling, and fibrosis. The signaling that differentiates the production of these opposing mediators is not understood. In this study, we find that the production of PGE2 and IL-6 following stimulation of human AECs by the damage-associated molecular pattern extracellular ATP shares a common requirement for Ca2+ release-activated Ca2+ (CRAC) channels. ATP-mediated synthesis of PGE2 required activation of metabotropic P2Y2 receptors and CRAC channel-mediated cytosolic phospholipase A2 signaling. By contrast, ATP-evoked synthesis of IL-6 occurred via activation of ionotropic P2X receptors and CRAC channel-mediated calcineurin/NFAT signaling. In contrast to ATP, which elicited the production of both PGE2 and IL-6, the uridine nucleotide, UTP, stimulated PGE2 but not IL-6 production. These results reveal that human AECs employ unique receptor-specific signaling mechanisms with CRAC channels as a signaling nexus to regulate release of opposing immunomodulatory mediators. Collectively, our results identify P2Y2 receptors, CRAC channels, and P2X receptors as potential intervention targets for airway diseases.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Dinoprostone / Interleukin-6 / Respiratory Mucosa / Inflammation Type of study: Prognostic study Limits: Humans Language: English Journal: J Immunol Year: 2021 Document Type: Article Affiliation country: Jimmunol.2100127

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Dinoprostone / Interleukin-6 / Respiratory Mucosa / Inflammation Type of study: Prognostic study Limits: Humans Language: English Journal: J Immunol Year: 2021 Document Type: Article Affiliation country: Jimmunol.2100127