Studies on cysteinyl leukotriene receptor 1 and 15-lipoxygenase-1 in lymphomas
Sammanfattning: Classical Hodgkin lymphoma (cHL) is a malignant disorder with striking inflammatory features. Since cysteinyl leukotrienes (cysLTs) are potent inflammatory mediators it was of interest to study their potential role in the pathogenesis of cHL. We have shown that certain HL cell lines express functional CysLT1 receptors, responding with a robust calcium signal upon leukotriene (LT) D4 challenge. Stimulation of these cells with LTD4 induced a CysLT1 receptor-dependent release of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha. The malignant Hodgkin Reed-Sternberg (H-RS) cells in the majority of the primary cHL biopsies under study also expressed the CysLT1 receptor. Since these cells are surrounded by cysLT-producing eosinophils, macrophages and mast cells, our results suggest that the cysLTs might be of importance for the pathogenesis of cHL (paper I). The cHL cell line L1236 has high expression of 15-lipoxygenase-1 (15-LO-1) and these cells were able to convert arachidonic acid to eoxin (EX) C4, EXD4 and EXE4, pro-inflammatory metabolites recently discovered in human eosinophils and mast cells. Immunohistochemical studies of cHL tumor tissue demonstrated that 15-LO-1 was expressed in primary H-RS cells in the majority of the investigated biopsies. Thus, the expression of 15-LO-1 and the formation of eoxins by H-RS cells are likely to contribute to the inflammatory features of cHL. These findings may have important diagnostic and therapeutic implications (paper II). The expression of the CysLT1 receptor and 15-LO-1 was also elucidated in non-Hodgkin lymphomas (NHLs). The majority of the primary mediastinal B cell lymphomas under study, in contrast to other NHLs, expressed the CysLT1 receptor. Furthermore, T cell-derived anaplastic large cell lymphoma was the only NHL entity shown to express 15-LO-1. Thus, the CysLT1 receptor and 15-LO-1 are potential targets in lymphoma diagnostics and sub-classification (paper III). Finally, we have studied the post-translational regulation of 15-LO-1 in dendritic cells. In the presence of calcium, addition of phosphatidylinositol-4.5-bisphosphate or phosphatidylinositol-3.4-bisphosphate to vesicles containing arachidonic acid led to a significantly increased formation of 15-hydroxyeicosa-5Z,8Z,11Z,13Etetraenoic acid (15-HETE) compared to vesicles without phosphoinositides. These results suggest that 15-LO-1 activity may also be regulated by the phospholipid constitution of membranes (paper IV).
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