title: Reed-Sternberg cell-derived lymphotoxin-α activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma.
abstract: It is known that cells within the inflammatory background in classical Hodgkin lymphoma (cHL) provide signals essential for the continual survival of the neoplastic Hodgkin and Reed-Sternberg (HRS) cells. However, the mechanisms underlying the recruitment of this inflammatory infiltrate into the involved lymph nodes are less well understood. In this study, we show in vitro that HRS cells secrete lymphotoxin-α (LTα) which acts on endothelial cells to upregulate the expression of adhesion molecules that are important for T cell recruitment. LTα also enhances the expression of hyaluronan which preferentially contributes to the recruitment of CD4(+) CD45RA(+) naïve T cells under in vitro defined flow conditions. Enhanced expression of LTα in HRS cells and tissue stroma; and hyaluronan on endothelial cells are readily detected in involved lymph nodes from cHL patients. Our study also shows that although NF-κB and AP-1 are involved, the cyclooxygenase (COX) pathway is the dominant regulator of LTα production in HRS cells. Using pharmacological inhibitors, our data suggest that activity of COX1, but not of COX2, directly regulates the expression of nuclear c-Fos in HRS cells. Our findings suggest that HRS cell-derived LTα is an important mediator that contributes to T cell recruitment into lesional lymph nodes in cHL.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore;
authors.forename: Chee Wai
authors.initials: CW
authors.lastname: Fhu
authors.affiliation: School of Medical Sciences, School of Life Sciences, University of Bradford, Bradford, United Kingdom;
authors.forename: Anne M
authors.initials: AM
authors.lastname: Graham
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; National University Cancer Institute, Singapore, Singapore;
authors.forename: Celestial T
authors.initials: CT
authors.lastname: Yap
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates;
authors.forename: Suhail
authors.initials: S
authors.lastname: Al-Salam
authors.affiliation: Tawam Hospital, Pathology Laboratories, Hematology Division, Al Ain, United Arab Emirates; and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Castella
authors.affiliation: Department of Pathology and.
authors.forename: Siew Meng
authors.initials: SM
authors.lastname: Chong
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; National University Cancer Institute, Singapore, Singapore; Department of Pathology and Immunology Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Yaw-Chyn
authors.initials: YC
authors.lastname: Lim
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D006689:Hodgkin Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism; D006820:Hyaluronic Acid / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000276:immunology / Q000378:metabolism*; D016539:Reed-Sternberg Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D015815:Cell Adhesion Molecules; D018960:Hyaluronan Receptors; D008233:Lymphotoxin-alpha; D006820:Hyaluronic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human