Leukotrienes Stimulate the Release of Cytokines and Proliferation of Hodgkin Reed-Sternberg Cells.

Background: Classical Hodgkin Lymphoma (cHL) is characterized by a minority of malignant cells, the so-called Hodgkin- and Reed Sternberg (H-RS) cells, surrounded by inflammatory cells such as eosinophils, macrophages and mast cells. In contrast to other tumors, the malignant H-RS cells constitute only a few percent of the total cells in the affected tissue. Therefore, it is generally believed that various compounds released by H-RS cells and the interaction between H-RS cells and by- stander cells are of great importance in the pathophysiology of cHL disease.

Aim: To characterize the expression and function of cysteinyl leukotriene receptors (CysLTR) in cHL.

Methods and results: We have identified functional CysLT1R in a HL cell line as shown by increased intracellular calcium release upon leukotriene (LT) D₄ stimulation (100–500 nM). This response was completely blocked after addition of zafirlukast, a specific CysLT1R antagonist. Immunohistochemical studies of paraffin embedded cHL tissue showed H-RS cells positive for CysLT1R in 12 of 16 cHL tumors. Microarray analysis of laser captured H-RS cells from 3 tumors not only confirmed the expression of CysLT1R transcripts, but also showed expression of the CysLT2R gene (P. Murray, personal communication). The possible role of the CysLT2R in H-RS cells will be discussed. The HL cell line was cultured in the presence of LTD₄ (100 nM) to investigate the effects of CysLT signaling in H-RS cells. Real-time RT-PCR analysis showed up-regulation of TNF-α, interleukin (IL)-6, IL-8 and IL-13 mRNA after stimulation with LTD₄. Furthermore, the effects of LTD₄ on cytokine protein secretion by the HL cells were studied by flow cytometry. The results showed a markedly increased secretion of TNF-α, IL-6 and IL-8 upon LTD₄ stimulation. In addition, LTD₄ stimulated cell proliferation in a dose-dependent manner.

Conclusion: Since H-RS cells are surrounded by CysLT producing cells (eosinophils, macrophages and mast cells), these results indicate that CysLT signaling could be of importance in the pathogenesis of cHL by contributing to proliferation of the tumor cell population and the disturbed cytokine features of this tumor. This study was supported by the Swedish Cancer Society.