IL-13 and IL-4 up-regulate cysteinyl leukotriene 1 receptor expression in human monocytes and macrophages

The cysteinyl (Cys) leukotrienes (LT)C-4, LTD4, and LTE4, are lipid mediato rs that have been implicated in the pathogenesis of asthma. The human LTD4 receptor (CysLT(1)R) was recently cloned and characterized. The present wor k was undertaken to study the potential modulation of CysLT(1)R expression by the Th2 cytokines IL-13 and IL-4. In this study, we report that IL-13 up -regulates CysLT(1)R mRNA levels, with consequently enhanced CysLT(1)R prot ein expression and function in human monocytes and monocyte-derived macroph ages. CysLT(1)R mRNA expression was augmented 2- to 5-fold following treatm ent with IL-13 and was due to enhanced transcriptional activity. The effect was observed after 4 h, was maximal by 8 h, and maintained at 24 h. IL-4, but not IFN-gamma, induced a similar pattern of CysLT(1)R up-regulation. Mo nocytes pretreated with IL-13 or IL-4 for 24 h showed enhanced CysLT(1)R pr otein expression, as assessed by flow cytometry using a polyclonal anti-Cys LT(1)R Ab. They also showed enhanced responsiveness to LTD4, but not to LTB 4, in terms of Ca2+ mobilization, as well as augmented chemotactic activity . Our findings suggest a possible mechanism by which IL-13 and IL-4 can mod ulate CysLT(1)R expression on monocytes and macrophages, and consequently t heir responsiveness to LTD4, and thus contribute to the pathogenesis of ast hma and allergic diseases.