leukotriene-b4 and Hodgkin-Disease

Primary effusion lymphoma (PEL) is a herpesvirus-8-associated lymphoproliferative disease characterized by migration of tumor cells to serous body cavities. PEL cells originate from postgerminal center B cells and share a remarkable alteration in B cell transcription factor expression and/or activation with classical Hodgkin's disease cells. Comparative analysis of gene expression by cDNA microarray of BCBL-1 cells (PEL), L-428 (classical Hodgkin's disease), and BJAB cells revealed a subset of genes that were differentially expressed in BCBL-1 cells. Among these, four genes involved in cell migration and chemotaxis were strongly up-regulated in PEL cells: leukotriene A4 (LTA4) hydrolase (LTA4H), IL-16, thrombospondin-1 (TSP-1), and selectin-P ligand (PSGL-1). Up-regulation of LTA4H was investigated at the transcriptional level. Full-length LTA4H promoter exhibited 50% higher activity in BCBL-1 cells than in BJAB or L-428 cells. Deletion analysis of the LTA4H promoter revealed a positive cis-regulatory element active only in BCBL-1 cells in the promoter proximal region located between -76 and -40 bp. Formation of a specific DNA-protein complex in this region was confirmed by EMSA. Coculture of ionophore-stimulated primary neutrophils with BCBL-1 cells leads to an increased production of LTB4 compared with coculture with BJAB and L-428 cells as measured by enzyme immunoassay, demonstrating the functional significance of LTA4H up-regulation.

Topics: Cell Line, Tumor; Enzyme Activation; Epoxide Hydrolases; Gene Expression Profiling; Hodgkin Disease; Humans; Inflammation; Interleukin-16; Leukotriene B4; Lymphoma, B-Cell; Membrane Glycoproteins; Promoter Regions, Genetic; RNA, Messenger; Thrombospondin 1; Transcription, Genetic; Up-Regulation

Metabolism of arachidonic acid in neutrophils was studied in vitro in blood samples obtained from 36 patients with Hodgkin's disease of various stage and histology and 32 healthy donors. The basic metabolites were: leucotriene B4, such products of its omega-oxidation as 20-hydroxy-leucotriene B4 (20-OH-LTB4) and 20-carboxy-leucotriene B4 (20-COOH-LTB4), and 5-hydroxyeicosatetraenic acid. Their profile proved identical in patients with Hodgkin's disease and healthy donors. Most patients with Hodgkin's disease showed a decrease in leucotriene B4 and 5-hydroxyeicosatetraenic acid and an increase in the level of omega oxidation of leucotriene B4 as assessed by omega catabolite/leucotriene B4 ratio. The levels of 5-hydroxyeicosatetraenic acid and leucotriene B4 omega-oxidation were found to depend upon histology and stage of Hodgkin's disease. They were nearly normal in patients with stage III, mixed cellular disease, B-symptoms and signs of biologic activity of tumor. A direct correlation was established between the level of leucotriene B4 omega oxidation in neutrophils and that of ceruloplasmin in blood serum of patients with various stages of Hodgkin's disease.

Topics: Adolescent; Adult; Arachidonic Acid; Arachidonic Acids; Ceruloplasmin; Cytochrome P-450 Enzyme System; Female; Hodgkin Disease; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Male; Middle Aged; Neutrophils; Oxidation-Reduction; Oxygenases