Yaddaden Louiza, Véronneau Steeve, Thompson Miles D, Rola-Pleszczynski Marek, Stankova Jana
Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
Prostaglandins Leukot Essent Fatty Acids. 2016 Feb;105:1-8. doi: 10.1016/j.plefa.2015.12.004. Epub 2015 Dec 21.
Cysteinyl-leukotrienes are pro-inflammatory lipid mediators, involved in allergic asthma, that bind the G-protein-coupled receptors CysLT1, CysLT2 and GPR99. A polymorphism in one of these receptors, CysLT1-G300S was strongly associated with atopy, whereas the CysLT1-I206S polymorphism was not. In the present work, our aim was to characterize these two variants by studying their cellular signalling. Cell surface expression of mutant receptors in transfected HEK-293 cells was comparable to that of the wild-type receptor. Compared to CysLT1-WT, production of inositol phosphates as well as IL-8 and IL-13 promoter transactivation in response to either LTD4 or LTC4 was significantly increased in CysLT1-G300S-transfected cells. Moreover, LTD4-induced phosphorylation of the signalling effector Erk, but not p38, p65 or c-Jun was higher in CysLT1-G300S-transfected cells. On the other hand, the variant CysLT1-I206S did not show a significant difference in its signal transduction compared to the wild-type receptor. Taken together, our results indicate that the variant CysLT1-G300S can induce a greater signal than the CysLT1-WT receptor, a feature that may be relevant to its association with atopy.
半胱氨酰白三烯是促炎性脂质介质，参与过敏性哮喘，可与G蛋白偶联受体CysLT1、CysLT2和GPR99结合。这些受体之一的CysLT1-G300S多态性与特应性密切相关，而CysLT1-I206S多态性则不然。在本研究中，我们旨在通过研究这两种变体的细胞信号传导来对其进行表征。转染的HEK-293细胞中突变受体的细胞表面表达与野生型受体相当。与CysLT1-WT相比，CysLT1-G300S转染细胞中，响应LTD4或LTC4时肌醇磷酸的产生以及IL-8和IL-13启动子的反式激活均显著增加。此外，CysLT1-G300S转染细胞中，LTD4诱导的信号效应器Erk的磷酸化水平较高，而p38、p65或c-Jun的磷酸化水平则不然。另一方面，与野生型受体相比，变体CysLT1-I206S在信号转导方面未显示出显著差异。综上所述，我们的结果表明，变体CysLT1-G300S比CysLT1-WT受体能诱导更强的信号，这一特性可能与其与特应性的关联有关。
