Evidence for a pathophysiological role of cysteinyl leukotrienes in classical Hodgkin lymphoma

Classical Hodgkin lymphoma (cHL) is characterized histologically by a minority of malignant Hodgkin Reed‐Sternberg cells surrounded by abundant inflammatory cells, generally believed to be of major importance in the pathophysiology of the disease. Here, we present data that link inflammatory cell‐derived arachidonic acid metabolites, the cysteinyl leukotrienes (CysLT), to the pathogenesis of cHL. Two HL cell lines, L1236 and KMH2, were shown to express functional CysLT1 receptors, responding with a robust calcium signal upon leukotriene (LT) D4 challenge. LTD4 stimulated protein release of tumor necrosis factor‐α, interleukin‐6 and ‐8 by L1236 cells and interleukin‐8 by KMH2 cells. Importantly, all these LTD4‐induced effects were blocked by the CysLT1 receptor‐specific antagonist zafirlukast. Immunohistochemical studies of cHL biopsies and microarray analysis of microdissected cells revealed that the CysLT1 receptor is expressed also by primary Hodgkin Reed‐Sternberg cells. As these cells are surrounded by CysLT‐producing eosinophils, macrophages and mast cells, our results suggest the CysLTs as mediators in the pathogenesis of cHL, contributing to the aberrant cytokine network of this lymphoma. © 2008 Wiley‐Liss, Inc.