IL-13 and IL-4 Up-Regulate Cysteinyl Leukotriene 1 Receptor Expression in Human Monocytes and Macrophages

Abstract

The cysteinyl (Cys) leukotrienes (LT)C₄, LTD₄, and LTE₄, are lipid mediators that have been implicated in the pathogenesis of asthma. The human LTD₄ receptor (CysLT₁R) was recently cloned and characterized. The present work was undertaken to study the potential modulation of CysLT₁R expression by the Th2 cytokines IL-13 and IL-4. In this study, we report that IL-13 up-regulates CysLT₁R mRNA levels, with consequently enhanced CysLT₁R protein expression and function in human monocytes and monocyte-derived macrophages. CysLT₁R mRNA expression was augmented 2- to 5-fold following treatment 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-γ, induced a similar pattern of CysLT₁R up-regulation. Monocytes pretreated with IL-13 or IL-4 for 24 h showed enhanced CysLT₁R protein expression, as assessed by flow cytometry using a polyclonal anti-CysLT₁R Ab. They also showed enhanced responsiveness to LTD₄, but not to LTB₄, 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 modulate CysLT₁R expression on monocytes and macrophages, and consequently their responsiveness to LTD₄, and thus contribute to the pathogenesis of asthma and allergic diseases.