title: Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4.
abstract: Leukotrienes (LTs) play major roles in lung immune responses, and LTD4 is the most potent agonist for cysteinyl LT1, leading to bronchoconstriction and tissue remodeling. Here, we studied LT crosstalk between myeloid cells and pulmonary epithelial cells. Monocytic cells (Mono Mac 6 cell line, primary dendritic cells) and eosinophils produced primarily LTC4 In coincubations of these myeloid cells and epithelial cells, LTD4 became a prominent product. LTC4 released from the myeloid cells was further transformed by the epithelial cells in a transcellular manner. Formation of LTD4 was rapid when catalyzed by γ-glutamyl transpeptidase (GGT)1 in the A549 epithelial lung cancer cell line, but considerably slower when catalyzed by GGT5 in primary bronchial epithelial cells. When A549 cells were cultured in the presence of IL-1β, GGT1 expression increased about 2-fold. Also exosomes from A549 cells contained GGT1 and augmented LTD4 formation. Serine-borate complex (SBC), an inhibitor of GGT, inhibited conversion of LTC4 to LTD4 Unexpectedly, SBC also upregulated translocation of 5-lipoxygenase (LO) to the nucleus in Mono Mac 6 cells, and 5-LO activity. Our results demonstrate an active role for epithelial cells in biosynthesis of LTD4, which may be of particular relevance in the lung.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Ana
authors.initials: A
authors.lastname: Lukic
authors.affiliation: Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Jie
authors.initials: J
authors.lastname: Ji
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Idborg
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Samuelsson
authors.affiliation: Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Palmberg
authors.affiliation: Department of Medicine Solna, Unit for Immunology and Allergy, Karolinska Institutet, 171 77 Stockholm, Sweden olof.radmark@ki.se susanne.gabrielsson@ki.se.
authors.forename: Susanne
authors.identifier: 0000-0003-1771-1346
authors.initials: S
authors.lastname: Gabrielsson
authors.affiliation: Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, 171 77 Stockholm, Sweden olof.radmark@ki.se susanne.gabrielsson@ki.se.
authors.forename: Olof
authors.identifier: 0000-0002-3424-3890
authors.initials: O
authors.lastname: Rådmark
mesh_terms: D000072283:A549 Cells; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001881:Borates / Q000008:administration & dosage; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D055354:Exosomes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D017997:Leukotriene C4 / Q000096:biosynthesis / Q000235:genetics*; D017998:Leukotriene D4 / Q000096:biosynthesis / Q000235:genetics*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D012694:Serine / Q000008:administration & dosage; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D001881:Borates; C040900:serine-borate complex; D017997:Leukotriene C4; D012694:Serine; D017998:Leukotriene D4; D001094:Arachidonate 5-Lipoxygenase; D005723:gamma-Glutamyltransferase
keywords: 5-lipoxygenase; arachidonic acid; cancer; eicosanoid; extracellular vesicles; inflammation; lung; macrophage/monocytes; γ-glutamyl transpeptidase