Novel Findings Support a Patophysiological Role of the Arachidonic Cascade in Hodgkin Lymphoma.

Abstract

Lipoxygenases (LO) are a family of structurally related enzymes which catalyze the conversion of the fatty acid arachidonic acid to biologically active metabolites. The key enzyme in leukotriene synthesis, 5- LO, catalyzes the first step in the metabolism of arachidonic acid to leukotriene (LT) C4. This compound and its metabolites LTD4 and LTE4, collectively called cysteinyl leukotrienes (cysLT), can bind to two high-affinity receptors, named cysLT1 and cysLT2. A sister enzyme to 5-LO is 15-LO-1 which also can catalyze the formation of bioactive metabolites. Arachidonic acid metabolites have traditionally been linked to inflammation and asthma but several studies also indicate a role of these metabolites in carcinogenesis In our studies of arachidonic acid metabolism in human lymphomas, we have identified the expression of 15-LO-1 and receptors for cysLT in primary as well as cultured Hodgkin-Reed Sternberg (H-RS) cells. In tumor tissue, H-RS cells positive for 15-LO-1 and the cysLT1 receptor were detected immunohistochemically in 13/15 and 12/16 cases, respectively. The presence of mRNA for 15-LO-1 and the cysLT1 and 2 receptors was confirmed by microarray analysis of laser dissected H-RS cells. Studies of 15-LO-1 gene transcription revealed that STAT6 activation and chromatin remodeling by DNA demethylation and histone acetylation are crucial for transcriptional activation of this gene in cultured H-RS cells. Incubation of the Hodgkin lymphoma-derived cell lines KMH2 and L1236 with LTD4 led to a robust calcium response that was completely abolished in presence of the cysLT1 receptor inhibitor zafirlukast. In L1236 cells, LTD4 induced increased DNA synthesis, interleukin-13 transcription and release of TNF-alpha, interleukin-6 and interleukin-8 in a dose-dependent manner, all of which were inhibited by zafirlukast. Thus, as the H-RS cells lack the expression of 5-LO, we hypothesize that that tumor-associated cysLT-producing inflammatory cells, such as eosinophils and mast cells, contribute to the pathogenesis of Hodgkin lymphoma through induction of tumor cell proliferation and cytokine release. Furthermore, immunohistochemical studies of 20 non-Hodgkin lymphomas revealed the expression of cysLT1 receptors also in primary mediastinal B cell lymphomas (PMBCL), and the functionality of these receptors was confirmed in the PMBCL-derived cell line MedB1. Taken together, these novel findings support a role for arachidonic acid metabolites in the pathogenesis of lymphoma.