Cysteinyl Leukotriene Receptor-1 Antagonists as Modulators of Innate Immune Cell Function

Figure 1

Cysteinyl leukotriene receptor-1-independent and -dependent anti-inflammatory activities of montelukast, pranlukast, and zafirlukast. The intracellular signalling pathways are depicted with the targets of the cysLTR1 antagonists indicated by means of a rectangle. Phospholipase A₂ (PLA₂) activation that is represented in pathway 1 during which membrane phospholipids are converted to arachidonic acid (AA), which is subsequently metabolized to either leukotrienes (LTA₄, LTB₄, and LTC₄) or prostaglandins (PGH₂) by 5-lipoxygenase (5-LO) and COX-1/2 enzymes, respectively. PGH₂ is converted to PGE₂ by PGE₂ synthase. Phospholipase (PLC) activation is represented in pathway 2 with the generation of inositol triphosphate (IP₃) which releases cytosolic Ca²⁺ from storage vesicles with subsequent downstream activation of PKC, NADPH oxidase, 5-LO, and NFκB, with release of proinflammatory cytokines. ATP binds to purinergic receptors (P2YR) and is also converted to cyclic AMP by adenylate cyclase (AC) which is degraded by intracellular phosphodiesterases (PDE). Cyclic AMP downregulates the Ca²⁺-mediated activation of 5-LO and NADPH oxidase. Inhibition of cysLTR1 receptors attenuates the receptor-dependent effects of cysteinyl leukotrienes.