NDLI: A role for inflammatory mediators in heterologous desensitization of $CysLT

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Capra, Valérie Accomazzo, Maria Rosa Gardoni, Fabrizio Barbieri, Silvia Rovati, G. Enrico
Description	Country affiliation: Italy Author Affiliation: Capra V ( Laboratory of Molecular Pharmacology, Università degli Studi di Milano, Milan, Italy.)
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.
File Format	HTM / HTML
ISSN	00222275
e-ISSN	15397262
DOI	10.1194/jlr.M003236
Journal	The Journal of Lipid Research
Issue Number	5
Volume Number	51
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-05-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Biochemistry Desensitization, Immunologic Inflammation Mediators Immunology Monocytes Receptors, Leukotriene Calcium Metabolism Cell Differentiation Drug Effects Cell Line Colforsin Dimethyl Sulfoxide Pharmacology Isoproterenol Cytology N-formylmethionine Leucyl-phenylalanine Peptides, Cyclic Receptors, G-protein-coupled Second Messenger Systems Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Endocrinology

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