Cysteinyl Leukotrienes and Their Receptors: Molecular and Functional Characteristics

Abstract

The cysteinyl leukotrienes (CysLTs) are a family of potent inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells including mast cells, eosinophils, basophils and macrophages. The family includes leukotriene C₄ (LTC₄), leukotriene D₄ (LTD₄) and leukotriene E₄ (LTE₄), which are potent biological mediators in the pathophysiology of inflammatory diseases and trigger contractile and inflammatory processes through the specific interaction with cell surface receptors, belonging to the superfamily of G-protein-coupled receptor. Pharmacological characterizations have suggested the existence of at least 2 types of CysLT receptors based on potency of agonist and antagonist, designated as CysLT₁ and CysLT₂. The CysLT₁ receptors are mostly expressed in lung smooth muscle cells, interstitial lung macrophages and the spleen, and it has been studied a lot elucidating its role in the etiology of airway inflammation and asthma. On the other hand, CysLT₂ receptors are present in the heart, brain and adrenal glands. This review discusses the role of CysLTs and their receptor in the pathophysiology of various inflammatory disorders. The understanding of CysLTs and their receptors in allergic airway disease is currently limited to CysLT₁-receptor-mediated effects, and the role of the CysLT₂ receptors is pharmacologically less well defined, as there is no specific antagonist available yet. Specific CysLT₂-receptor-selective antagonists would be very helpful to identify the precise role of CysLT and their receptors. Some recent evidence indicates the existence of additional receptor subtypes and requires further investigation for a better understanding of the role of the CysLT receptors. This review is an effort to summarize the localization, regulation and expression pattern along with the molecular and functional pharmacology of the CysLT receptors and to discuss their role in the pathophysiology of different diseases along with the recent update.

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

“…In this sense, it has been demonstrated in several tissues that the expression of both receptors can be regulated by CysLT release. 18,50 The use of montelukast did not allow us to block the production of IL-23, indicating that it could be modulated by the action of LTC 4 through the CysLTR2. This point could not be evaluated; because there is still no specific receptor antagonist.…”

“…54 Binding of CysLT with their receptors triggers the phosphorylation of MAPK. 18,19 Hashimoto et al 55 demonstrated that IL-10 production in human DCs stimulated with Zy was dependent on ERK and p38 MAPK activation. Also, the phagocytosis of opsonized particles by macrophages cultured with LTD 4 or LTC 4 was associated with p38 activation.…”

“…[15][16][17] The pharmacological effects of CysLT are conducted through two types of membrane receptorsCysLTR1 and CysLTR2 -which are coupled to protein-G. 18 Remarkably, these receptors were primarily described at the level of lung mucosa and intestinal mucosa at the ileum and colon. 19 In many diseases affecting lung and intestinal mucosa, such as asthma and interstitial cystitis, the use of montelukast, a selective antagonist of CysLTR1, minimizes the effects of these pathologies, probably through the inhibition of cytosolic Ca 2+ .…”

“…18 Expression of CysLTR1 has been demonstrated in murine DCs. 40 Our objective was to evaluate the expression of both receptors in immature and LPS-stimulated DCs by reverse transcription (RT-) PCR.…”

Hydrolysis of S-aryl-cysteinylglycine conjugates catalyzed by porcine kidney cortex membrane dipeptidase

“…The CCNAT co-substrate acetyl-CoA is localized in the cytosol at high concentrations to facilitate rapid and efficient N-acetylation of Cys conjugates (Garland et al, 1965). CCNAT is also involved in the metabolism of the cysteinyl leukotrienes C 4 , D 4 , and E 4 ; these fatty lipid-rich molecules play a role in the inflammation response of the immune system (Singh et al, 2010).…”