Cysteinyl Leukotrienes and Their Receptors: Cellular Distribution and Function in Immune and Inflammatory Responses

Abstract

The cysteinyl leukotrienes (cys-LTs) are a family of potent bioactive lipids that act through two structurally divergent G protein-coupled receptors, termed the CysLT1 and CysLT2 receptors. The cloning and characterization of these two receptors has not only reconciled findings of previous pharmacologic profiling studies of contractile tissues, but also has uncovered their expression on a wide array of circulating and tissue-dwelling leukocytes. With the development of receptor-selective reagents, as well as mice lacking critical biosynthetic enzymes, transporter proteins, and the CysLT1 receptor, diverse functions of cys-LTs and their receptors in immune and inflammatory responses have been identified. We review cys-LT biosynthesis; the molecular biology and distribution of the CysLT1 and CysLT2 receptors; the functions of cys-LTs and their receptors in the recruitment and activation of effector leukocytes and induction of adaptive immunity; and the development of fibrosis and airway remodeling in animal models of lung injury and allergic inflammation.

Leukotriene D4 induces gene expression in human monocytes through cysteinyl leukotriene type I receptor

“…LTC 4 , LTD 4 , LTE 4 , and MK571 (Cayman Chemical, Ann Arbor, Mich); pertussis toxin (Biomol, Plymouth Meeting, Pa); 2APB, U73122, SB203580, SB202190, PD98059, U0126, ethyleneglycolbis-(β-aminoethylether)-N,N,N′,N′-tetraacetic acid (EGTA), and BAPTA/AM (EMD Biosciences, San Diego, Calif); anti-phospho-p38 mitogen-activated protein kinase (MAPK), anti-phospho-p44/42 MAPK, anti-p38 MAPK, and anti-p44/42 MAPK antibodies (Cell Signaling, Danvers, Mass); anti-β actin antibody (Sigma-Aldrich, St Louis, Mo); and peroxidase-conjugated anti-rabbit antibodies (Jackson Immunoresearch, West Grove, Pa) were obtained from the manufacturers.…”

“…As expected, the expression of all studied genes was upregulated by LTD 4 stimulation, with higher changes observed in real-time PCR than in microarray experiments. The 2 most highly upregulated genes were analyzed for transcript kinetics by using real-time PCR to further verify the pattern of gene upregulation induced by LTD 4 . LTD 4 induced a significant increase in the mRNA levels of FBJ murine osteosarcoma viral oncogene homolog B (FOSB) and Egr2 in a time-dependent fashion, with the highest increase observed between 30 and 60 minutes and returning to baseline after 2 hours (Fig 1).…”

“…However, a recent study in mice demonstrated that monocytes can process antigen in the bone marrow and effectively present it later in lymph nodes, suggesting their direct involvement in the immune response to antigens. 3 Cysteinyl leukotrienes (CysLTs; leukotriene [LT] C 4 , LTD 4 , and LTE 4 ) are lipid mediators derived from arachidonic acid through the 5-lipoxygenase pathway that are involved in pathogenesis of a variety of chronic inflammatory disorders, including bronchial asthma, allergic rhinitis, pulmonary fibrosis, and atherosclerosis. 4,5 The biologic actionsof CysLTs can be mediated through3 known G protein-coupled receptors: the CysLT type 1 (CysLTR 1 ) 6 and type 2 (CysLTR 2 ) 7 receptors and the recently described receptor GPR17.…”

“…3 Cysteinyl leukotrienes (CysLTs; leukotriene [LT] C 4 , LTD 4 , and LTE 4 ) are lipid mediators derived from arachidonic acid through the 5-lipoxygenase pathway that are involved in pathogenesis of a variety of chronic inflammatory disorders, including bronchial asthma, allergic rhinitis, pulmonary fibrosis, and atherosclerosis. 4,5 The biologic actionsof CysLTs can be mediated through3 known G protein-coupled receptors: the CysLT type 1 (CysLTR 1 ) 6 and type 2 (CysLTR 2 ) 7 receptors and the recently described receptor GPR17. 8 CysLTs have been recognized primarily as mediators involved in the development of phenotypes characteristic for bronchial asthma, such as bronchoconstriction, mucus secretion, and bronchial hyperresponsiveness.…”

“…mRNA of both CysLTR 1 and CysLTR 2 has been detected in human monocytes, and it was reported that LTD 4 can induce intracellular calcium flux and chemotactic activity through CysLTR 1 in peripheral blood monocytes. 12,18 Nonetheless, the signal transduction pathways used by CysLTR 1 and other CysLT receptors, as well as the precise role in the immune response of human monocytes, has not been fully addressed.…”