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.
Highlights
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
LTC4 synthase (LTC4S) is primarily located at the nuclear membrane together with 5-lipoxygenase activating protein (FLAP), and both proteins are members of the family of membrane bound proteins involved in eicosanoid and glutathione metabolism (MAPEG)
Mono Mac 6 (MM6) cells were differentiated with TGF and VD3 for 72 h, which leads to upregulation of 5-LO [2], and A549 cells were starved and stimulated with IL-1 for 48 h
Summary
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. 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. Formation of LTD4 was rapid when catalyzed by -glutamyl transpeptidase (GGT) in the A549 epithelial lung cancer cell line, but considerably slower when catalyzed by GGT5 in primary bronchial epithelial cells. -Glutamyl transpeptidase (GGT) and GGT5 are cell surface enzymes that hydrolyze -glutamyl compounds, typically in glutathione metabolism, and the conversion of LTC4 to LTD4 [7,8,9,10]. GGT activity and GGT1 mRNA was found in the nonsmall lung cancer cell line, A549 [13, 14]. GGT5 was found in macrophages present in human tissues, most abundant in the lung [19]
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