title: Interleukin-4 distinctively modifies responses of germinal centre-like and activated B-cell-like diffuse large B-cell lymphomas to immuno-chemotherapy.
abstract: Diffuse large B-cell lymphomas (DLBCLs) can be classified into two subtypes: germinal-centre B-cell (GCB)-like and Activated B-cell (ABC)-like tumours, which are associated with longer or shorter patient overall survival, respectively. In our previous studies, we have shown that, although DLBCL tumours of GCB-like and ABC-like subtypes express similar levels of IL4 mRNA, they exhibit distinct patterns of IL-4-induced intracellular signalling and different expression of IL-4 target genes. We hypothesized that these differences may contribute to the different clinical behaviour and outcome of DLBCL subtypes. Herein, we demonstrated that IL-4 increased the sensitivity of GCB-like DLBCL to doxorubicin-induced apoptosis and complement-dependent rituximab cell killing. In contrast, IL-4 protected ABC-like DLBCL from the cytotoxic effects of doxorubicin and rituximab. The distinct effects of IL-4 on doxorubicin sensitivity in GCB-like and ABC-like DLBCL cells may be partially attributed to the contrasting effects of the cytokine on Bcl-2 and Bad protein levels in the DLBCL subtypes. These findings suggest that the different effects of IL-4 on chemotherapy and immunotherapy-induced cytotoxicity of GCB- and ABC-like DLBCL could contribute to the different clinical outcomes exhibited by patients with these two subtypes of DLBCL.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
authors.forename: Kristopher A
authors.initials: KA
authors.lastname: Sarosiek
authors.forename: Hovav
authors.initials: H
authors.lastname: Nechushtan
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Lu
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Rosenblatt
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018858:Germinal Center / Q000473:pathology*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D000069283:Rituximab; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D015847:Interleukin-4; D000069283:Rituximab; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases
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