Abstract
Cysteinyl-leukotrienes (cysteinyl-LT) are rapidly generated at sites of inflammation and, in addition to their role in asthma, rhinitis, and other immune disorders, are increasingly regarded as significant inflammatory factors in cancer, gastrointestinal, cardiovascular diseases. We recently demonstrated that in monocyte/macrophage-like U937 cells, extracellular nucleotides heterologously desensitize CysLT(1) receptor (CysLT(1)R)-induced Ca(2+) transients. Given that monocytes express a number of other inflammatory and chemoattractant receptors, this study was aimed at characterizing transregulation between these different stimuli. We demonstrate that in U937 cells and in primary human monocytes, a series of inflammatory mediators activating G(i)-coupled receptor (FPR1, BLT(1)) desensitize CysLT(1)R-induced Ca(2+) response unidirectionally through activation of PKC. Conversely, PAF-R, exclusively coupled to G(q), cross-desensitizes CysLT(1)R without the apparent involvement of any kinase. Interestingly, G(s)-coupled receptors (beta(2)AR, H(1/2)R, EP(2/4)R) are also able to desensitize CysLT(1)R response through activation of PKA. Heterologous desensitization seems to affect mostly the G(i)-mediated signaling of the CysLT(1)R. The hierarchy of desensitization among agonists may be important for leukocyte signal processing at the site of inflammation. Considering that monocytes/macrophages are likely to be the major source of cysteinyl-LT in many immunological and inflammatory processes, shedding light on how their receptors are regulated will certainly help to better understand the role of these cells in orchestrating this complex network of integrated signals.
Highlights
We demonstrate that in U937 cells and in primary human monocytes, a series of inflammatory mediators activating iGnid-cuocuepdleCda2r+erceespptoonrs(eFuPnRid1,irBecLtTio1n)adlleystehnrsoiutigzhe
Given that monocytes/macrophages besides CysLT1 receptor (CysLT1R) and P2Y-R express a number of other inflammatory and chemoattractant receptors, such as those for LTB4 (BLT1R), formyl-methionyl-leucyl phenylalanine (fMLF), FPR1, platelet activating factor (PAF-R), histamine H (H1/2R), and prostaglandin E2 (EP2/4R) or inflammatory-related receptors, such as 2 adrenoreceptor (2AR) [20], this study was aimed at characterizing transregulation between these different stimuli [13, 28]
It is widely known that leukotriene D4 (LTD4) elicits a cytosolic Ca2+ transient ([Ca2+]i) in DMSO-differentiated U937 cells through the activation of the CysLT1R promiscuously coupled to both Gq and Gi [16, 29, 30]
Summary
We demonstrate that in U937 cells and in primary human monocytes, a series of inflammatory mediators activating iGnid-cuocuepdleCda2r+erceespptoonrs(eFuPnRid1,irBecLtTio1n)adlleystehnrsoiutigzhe. Cysteinyl-leukotrienes (cysteinyl-LT) (i.e., LTC4, LTD4, and LTE4) are members of a large family of biologically active lipid mediators rapidly generated at sites of inflammation from arachidonic acid via the 5-lipoxygenase (5-LO) pathway [1]. They are synthesized by inflammatory cells, such as eosinophils, basophils, mast cells, and alveolar macrophages, in response to different immune and inflammatory stimuli [2]. Beyond their well-recognized role in asthma and immune disorders, cysteinyl-LTs are increasingly regarded as significant inflammatory factors in cancer, gastrointestinal, and cardiovascular diseases [3]. Several data in the literature suggested the existence of additional CysLT receptor (CysLT-R) subtypes in humans [3], and very recently new pharmacological targets have been identified for cysteinylLTs, namely, two possible new receptor entities [8, 9] and a CysLT1/CysLT2 heterodimer [10]
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