title: Early growth response gene (EGR)-1 regulates leukotriene D4-induced cytokine transcription in Hodgkin lymphoma cells.
abstract: Classical Hodgkin lymphoma (cHL) has a unique pathological feature characterized by a minority of malignant Hodgkin Reed-Sternberg (H-RS) cells surrounded by numerous inflammatory cells. Cysteinyl-leukotrienes (CysLTs) are produced by eosinophils, macrophages and mast cells in the HL tumor microenvironment. In the present study we have explored the signal transduction pathways leading to leukotriene (LT) D4 induced expression of cytokines in the Hodgkin lymphoma cell line L1236 and KM-H2. Stimulation of L1236 and KM-H2 cells with LTD4 led to a concentration- and time-dependent increase at the transcriptional level of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8, chemokine (C-C motif) ligand 3 (CCL3) and CCL4. The expression of several transcription factors was induced upon stimulation of Hodgkin cell lines with LTD4. Among these, EGR-1 was required for cytokine production. Inhibition of EGR-1 expression using shEGR-1 transduced by lentivirus led to suppression of the expression of TNF-α and IL-6. The effect of LTD4 on the expression of transcription factors and cytokines were also blocked by the specific CysLT1 receptor antagonist zafirlukast. These results demonstrate that EGR-1 plays a critical role in LTD4-induced cytokine transcription in Hodgkin cell lines.
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden. Electronic address: Ya.Han@ki.se.
authors.forename: Hongya
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Xue-Franzén
authors.affiliation: Department of Medicine, Clinical Pharmacology Group, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Miao
authors.affiliation: Department of Medicine, KI, Department of Cardiology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Edit
authors.initials: E
authors.lastname: Nagy
authors.affiliation: Department of Medicine, Clinical Pharmacology Group, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nailin
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Sjöberg
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Björkholm
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hans-Erik
authors.initials: HE
authors.lastname: Claesson
mesh_terms: D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics*; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006689:Hodgkin Disease / Q000235:genetics / Q000473:pathology*; D006801:Humans; D017998:Leukotriene D4 / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D016207:Cytokines; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C083169:leukotriene D4 receptor
keywords: Cysteinyl leukotriene receptors; Early growth response 1; Hodgkin lymphoma; Leukotrienes