1. Reed-Sternberg cell-derived lymphotoxin-α activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma.
- Author
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Fhu CW, Graham AM, Yap CT, Al-Salam S, Castella A, Chong SM, and Lim YC
- Subjects
- CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cell Adhesion Molecules immunology, Cell Adhesion Molecules metabolism, Cell Line, Cyclooxygenase 2 immunology, Cyclooxygenase 2 metabolism, Endothelial Cells immunology, Endothelial Cells metabolism, Hodgkin Disease immunology, Hodgkin Disease pathology, Human Umbilical Vein Endothelial Cells, Humans, Hyaluronan Receptors immunology, Hyaluronan Receptors metabolism, Hyaluronic Acid immunology, Hyaluronic Acid metabolism, Lymph Nodes immunology, Lymph Nodes metabolism, Lymph Nodes pathology, Lymphotoxin-alpha immunology, Reed-Sternberg Cells immunology, Reed-Sternberg Cells metabolism, CD4-Positive T-Lymphocytes cytology, Cell Communication immunology, Endothelial Cells cytology, Hodgkin Disease metabolism, Lymphotoxin-alpha metabolism, Reed-Sternberg Cells cytology
- 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., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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