title: Ozone modulates IL-6 secretion in human airway epithelial and smooth muscle cells.
abstract: Although ozone enhances leukocyte function and recruitment in airways, the direct effect of ozone in modulating structural cell-derived inflammatory mediators remains unknown. Using a coculture model comprised of differentiated human airway epithelial cells (NHBE) and smooth muscle cells (ASM), we postulate that ozone regulates IL-6 secretion in basal and cytokine-primed structural cells. Air-liquid interface (ALI) cultures of NHBE cells underwent differentiation as determined by mucin secretion, transepithelial electrical resistance (TEER), and ultrastructure parameters. Whereas TNF enhanced basal secretion of IL-6 (57 +/- 3%), ozone exposure at 0.6 ppm for 6 h augmented IL-6 levels in basal (41 +/- 3%) and TNF- (50 +/- 5%) primed cocultures compared with that derived from NHBE or ASM monolayers alone. Levels of PGE(2), 6-keto-PGF(1alpha), PGF(2alpha), and thromboxane B(2) (TxB(2)) levels in basal and TNF-primed cocultures revealed that ozone selectively enhanced PGE(2) production in TNF- (6 +/- 3-fold) primed cocultures, with little effect (P > 0.05) on diluent-treated cultures. In accordance with ozone-induced increases in PGE(2) levels, cyclooxygenase inhibition with indomethacin partially abolished IL-6 secretion. Surprisingly, indomethacin had little effect on constitutive secretion of IL-6 in cocultures, whereas indomethacin completely restored ozone-mediated TEER reduction in TNF-primed cocultures. Collectively, our data for the first time suggest a dual role of ozone in modulating IL-6 secretion and TEER outcomes in a PGE(2)-dependent (in presence of TNF stimulus) and -independent manner (in absence of cytokine stimulus).
authors.affiliation: University of Pennsylvania, Philadelphia, PA 19104-3403, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Damera
authors.forename: Hengjiang
authors.initials: H
authors.lastname: Zhao
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Smith
authors.forename: Christopher
authors.initials: C
authors.lastname: Kirby
authors.forename: William F
authors.initials: WF
authors.lastname: Jester
authors.forename: John A
authors.initials: JA
authors.lastname: Lawson
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018920:Coculture Techniques; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D017097:Electric Impedance; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D008168:Lung / Q000166:cytology*; D009077:Mucins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism*; D010126:Ozone / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D015850:Interleukin-6; D009077:Mucins; D014409:Tumor Necrosis Factor-alpha; D010126:Ozone; D015232:Dinoprostone; D007213:Indomethacin