title: Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation.
abstract: We investigated the effects of bendamustine on B cell functions and explored potential clinical applications of the drugs to autoimmune diseases. Proliferation of Ramos cells, a human B cell line, was significantly inhibited by 25-100μM of bendamustine in a dose-dependent manner. Concordantly, IgM secretion from Ramos cells was significantly inhibited at these concentrations by up to 70%. Interestingly, however, the production and secretion of interleukin-10 (IL-10) were dramatically (at least >10-fold) increased by bendamustine at growth inhibitory concentrations. Exploration of the molecular mechanism of IL-10 production revealed that bendamustine enhanced the phosphorylation of p38 MAP kinase. Further, Sp1 was identified as a downstream transcription factor, and the inhibition of p38 MAP kinase and Sp1 with their inhibitors led to the abrogation of bendamustine-induced IL-10 production and the DNA binding of Sp1. Importantly, when PBMC from healthy donors were cultured with bendamustine at the concentration of 30μM, under the stimulation with an anti-IgM antibody, an anti-CD40 antibody, recombinant human IL-21 (rhIL-21) and recombinant human soluble BAFF (rhsBAFF), IL-10 production by B cells (CD20+CD4-CD8-CD14-) among peripheral blood mononuclear cell (PBMC) was significantly enhanced by adding bendamustine. These results collectively suggest that the p38 MAP kinase-Sp1 pathway plays a crucial role in bendamustine-induced IL-10 production by B cells. Our findings suggest a novel therapeutic possibility for autoimmune diseases through the upregulation of IL-10 which has an anti-inflammatory effects.
authors: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 1608582, Japan; Department of Integrative Medicine, Jinling Hospital, Nanjing, Jiangsu Province 210002, China. Electronic address: merry_lu66@163.com.
authors: Le
authors: L
authors: Lu
authors: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 1608582, Japan.
authors: Keiko
authors: K
authors: Yoshimoto
authors: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 1608582, Japan.
authors: Atsuho
authors: A
authors: Morita
authors: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 1608582, Japan; Division of Rheumatology, Department of Internal Medicine, Toho University, Tokyo 1538515, Japan.
authors: Hideto
authors: H
authors: Kameda
authors: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 1608582, Japan.
authors: Tsutomu
authors: T
authors: Takeuchi
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D018951:Antigens, CD20 / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D000069461:Bendamustine Hydrochloride / Q000494:pharmacology*; D002454:Cell Differentiation; D002460:Cell Line; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D007378:Interleukins / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D000888:Antibodies, Anti-Idiotypic; D018951:Antigens, CD20; D018906:Antineoplastic Agents, Alkylating; D007378:Interleukins; D016329:Sp1 Transcription Factor; C044203:anti-IgM; D016753:Interleukin-10; D000069461:Bendamustine Hydrochloride; D048051:p38 Mitogen-Activated Protein Kinases; D000098546:Interleukin-21
keywords: B cells; Bendamustine; Interleukin-10; p38 MAP kinase