Leukotriene E4 Activates Peroxisome Proliferator-activated Receptor γ and Induces Prostaglandin D2 Generation by Human Mast Cells

Abstract

sensitive to interference by the PPAR␥ antagonist GW9662 and to targeted knockdown of PPAR␥. Although LTE 4 -mediated PGD 2 production was also sensitive to MK571, an antagonist for the type 1 receptor for cys-LTs (CysLT 1 R), it was resistant to knockdown of this receptor. This LTE 4 -selective receptor-mediated pathway may explain the unique physiologic responses of human airways to LTE 4 in vivo.Cysteinyl leukotrienes (cys-LTs) 2 (LTC 4 , LTD 4 , LTE 4 ) are potent inflammatory mediators derived from arachidonic acid and generated by mast cells (MCs), eosinophils, basophils, and macrophages (reviewed in Ref. 1). Arachidonic acid is liberated from nuclear membrane phospholipids by a cytosolic phospholipase A 2 (2) and converted by 5-lipoxygenase (5-LO) and its molecular partner, 5-LO-activating protein (FLAP), to the unstable intermediate LTA 4 at the nuclear envelope (3, 4). LTA 4 is then conjugated to reduced glutathione by an integral nuclear membrane protein, leukotriene C 4 synthase (LTC 4 S) (5, 6), forming LTC 4 . After transport to the extracellular space by multidrug resistance protein-1 (7), LTC 4 is converted extracellularly to LTD 4 by a ␥-glutamyl leukotrienase (8), and then to the terminal product LTE 4 by a dipeptidase (9). This rapid conversion ensures that LTC 4 and LTD 4 are very short-lived in vivo. In contrast, LTE 4 is stable, being the only cys-LT detected in biologic fluids and excreted in the urine without further modification (10). Cys-LTs are the most potent known bronchoconstrictors (11, 12), and they also potentiate airway hyperresponsiveness (AHR) to histamine when they are administered by inhalation to human subjects (13). Bronchoalveolar lavage (BAL) fluids collected from allergen-challenged atopic asthmatic individuals contain high levels of cys-LTs (14), and levels of LTE 4 are elevated in urine samples from patients during spontaneous asthmatic exacerbations (10). Drugs that block the type 1 receptor for cys-LTs (CysLT 1 R) (15,16) or that interfere with cys-LT synthesis (17) are clinically efficacious in asthma. Studies with mice lacking LTC 4 S and/or cys-LT receptors suggest additional prominent functions for these mediators in adaptive immunity and fibrosis (18 -20). Thus, mechanisms that control cys-LT-dependent biologic responses are of considerable pathobiologic and clinical interest in both allergic and nonallergic disease.CysLT 1 R and CysLT 2 R are the two known G protein-coupled receptors (GPCRs) selective for cys-LTs (21,22). CysLT 1 R is expressed prominently by smooth muscle and leukocytes (22, 23), while CysLT 2 R is expressed by cardiac Purkinje cells, endo-*

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…In contrast, LTE 4 failed to activate a CysLTR in human pulmonary vessels (Walch et al, 2002). In 2008, the first report that LTE 4 mediated prostaglandin D 2 production, which was sensitive to the CysLT 1 R antagonist MK-571 but resistant to knock down of this receptor, was published (Paruchuri et al, 2008). Furthermore, this effect, induced through COX-2 induction and ERK, p90RSK, and cAMP-regulated-binding protein phosphorylation, was not mediated by LTD 4 but was sensitive to PPAR-␥ knockdown, suggesting the 568 presence of a LTE 4 -selective receptor in human MCs (Paruchuri et al, 2008).…”

“…In 2008, the first report that LTE 4 mediated prostaglandin D 2 production, which was sensitive to the CysLT 1 R antagonist MK-571 but resistant to knock down of this receptor, was published (Paruchuri et al, 2008). Furthermore, this effect, induced through COX-2 induction and ERK, p90RSK, and cAMP-regulated-binding protein phosphorylation, was not mediated by LTD 4 but was sensitive to PPAR-␥ knockdown, suggesting the 568 presence of a LTE 4 -selective receptor in human MCs (Paruchuri et al, 2008). Almost simultaneously it was demonstrated that intradermal injection of LTE 4 into the ear of mice deficient in both CysLT 1 R/CysLT 2 R elicited a vascular leak that exceeded the response to intradermal injection of LTC 4 or LTD 4 and that this response was inhibited by pretreatment of the mice with PTX or a Rho kinase inhibitor (Maekawa et al, 2008).…”

Differential Signaling of Cysteinyl Leukotrienes and a Novel Cysteinyl Leukotriene Receptor 2 (CysLT2) Agonist, N-Methyl-Leukotriene C4, in Calcium Reporter and β Arrestin Assays

“…The biased nature of agonist signaling through one receptor (Violin and Lefkowitz, 2007) is not without precedence; the -opioid receptor (Keith et al, 1996) is one well characterized example. These results with LTE 4 are significant given the recent de- termination of a (putative) LTE 4 -selective receptor (CysLT E ) and that LTE 4 can apparently act via non-GPCR pathways (e.g., peroxisome proliferator-activated receptor-␥) (Paruchuri et al, 2008). LTE 4 signaling via the hCysLT 2 receptor apparently displays preference toward trimeric G-protein signaling rather than via ␤-arrestin 2 pathways, as evidenced by the calcium activity but lack of ␤-arrestin 2 association.…”

The Responses of Pulmonary and Systemic Circulation and Airway to Allergic Mediators in Anesthetized Rats

“…The cysteinyl LT binds to the cysteinyl LT receptors 1, 2, and 3 or the cysteinyl LT receptor E4. [35][36][37] Cysteinyl LTs evoke contradictory effects on vascular tone, depending on the species and the experimental preparations, 38) via both endothelium-and smooth muscle-dependent actions. The functional roles of these cysteinyl LT receptors in regulation of pulmonary vessels still remain unknown.…”