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 CysLT(1) receptors, responding with a robust calcium signal upon leukotriene (LT) D(4) challenge. LTD(4) stimulated protein release of tumor necrosis factor-alpha, interleukin-6 and -8 by L1236 cells and interleukin-8 by KMH2 cells. Importantly, all these LTD(4)-induced effects were blocked by the CysLT(1) receptor-specific antagonist zafirlukast. Immunohistochemical studies of cHL biopsies and microarray analysis of microdissected cells revealed that the CysLT(1) 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.
Schain
Frida
F
Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden. frida.schain@ki.se
Tryselius
Ylva
Y
Sjöberg
Jan
J
Porwit
Anna
A
Backman
Linda
L
Malec
Maria
M
Xu
Dawei
D
Vockerodt
Martina
M
Baumforth
Karl R N
KR
Wei
Wenbin
W
Murray
Paul G
PG
Björkholm
Magnus
M
Claesson
Hans-Erik
HE
D000293:Adolescent; D000328:Adult; D000368:Aged; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003545:Cysteine / Q000737:chemistry*; D005260:Female; D006689:Hodgkin Disease / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D017998:Leukotriene D4 / Q000494:pharmacology; D015289:Leukotrienes / Q000737:chemistry / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism
D015289:Leukotrienes; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; D003545:Cysteine; C083169:leukotriene D4 receptor