title: Functional coexpression of Interleukin (IL)-7 and its receptor (IL-7R) on Hodgkin and Reed-Sternberg cells: Involvement of IL-7 in tumor cell growth and microenvironmental interactions of Hodgkin's lymphoma.
abstract: The clinical and pathological features of classical Hodgkin lymphoma (cHL) mirror an abnormal tissue and systemic immune response due to the production of a variety of cytokines and chemokines by the malignant Hodgkin-Reed-Sternberg (H-RS) cells and/or surrounding reactive cells. Here, we demonstrate that HL-derived cell lines (L-428, KM-H2, HDLM-2, L-1236 and L-540) and primary H-RS cells from lymph node tissues of HL patients express the IL-7(R) receptor. IL-7 appears to be involved in autocrine circuitries of HL because L-1236, HDLM-2 and KM-H2 cells display the constitutive production of IL-7 and neutralizing anti-IL-7 antibodies induces a statistically significant inhibition of their basal proliferation. In addition, IL-7, either exogenous or fibroblasts-derived, promotes the clonogenic growth and reduces apoptosis of cultured H-RS cells, being also able to partially protect these cells from the cytotoxic effects of doxorubicin. We also provide evidence that IL-7 stimulates IL-6 secretion from IL-7R-expressing fibroblasts from HL-involved lymph nodes (HLFs), and that a striking increase in IL-6 secretion can be observed in cocultures of HLFs with L1236 cells. Finally, we show that L-1236 cells-derived IL-7 represents a costimulator for proliferation of purified CD4+CD25+CD127(dim/-) regulatory T cells (Tregs). Taken together, our data indicates that the IL-7/IL-7R axis constitutes an additional signaling pathway between H-RS cells and their reactive cellular background, thereby affecting proliferation and survival of tumor cells, acting as a cofactor for Tregs expansion and enhancing the microenviromental production of IL-6, a cytokine associated with the presence of "B" symptoms and a poor outcome in HL patients.
authors.affiliation: Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Cattaruzza
authors.forename: Annunziata
authors.initials: A
authors.lastname: Gloghini
authors.forename: Karin
authors.initials: K
authors.lastname: Olivo
authors.forename: Raffaele
authors.initials: R
authors.lastname: Di Francia
authors.forename: Debora
authors.initials: D
authors.lastname: Lorenzon
authors.forename: Rosaria
authors.initials: R
authors.lastname: De Filippi
authors.forename: Antonino
authors.initials: A
authors.lastname: Carbone
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.forename: Antonio
authors.initials: A
authors.lastname: Pinto
authors.forename: Donatella
authors.initials: D
authors.lastname: Aldinucci
mesh_terms: D017209:Apoptosis; D019898:Autocrine Communication; D015153:Blotting, Western; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D006689:Hodgkin Disease / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D016539:Reed-Sternberg Cells / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: D015851:Interleukin-7; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7