Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation

Le Lu, Keiko Yoshimoto, Atsuho Morita, Hideto Kameda, Tsutomu Takeuchi

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 25–100 μM 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 30 μM, 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.

Original languageEnglish
Pages (from-to)273-279
Number of pages7
JournalInternational Immunopharmacology
Volume39
DOIs
Publication statusPublished - 2016 Oct 1

Fingerprint

p38 Mitogen-Activated Protein Kinases
Interleukin-10
B-Lymphocytes
Autoimmune Diseases
Anti-Idiotypic Antibodies
Blood Cells
Bendamustine Hydrochloride
Immunoglobulin M
Anti-Inflammatory Agents
Transcription Factors
Up-Regulation
Phosphorylation
Cell Proliferation
Cell Line
DNA
Growth
Pharmaceutical Preparations

Keywords

  • B cells
  • Bendamustine
  • Interleukin-10
  • p38 MAP kinase

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Pharmacology

Cite this

Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation. / Lu, Le; Yoshimoto, Keiko; Morita, Atsuho; Kameda, Hideto; Takeuchi, Tsutomu.

In: International Immunopharmacology, Vol. 39, 01.10.2016, p. 273-279.

Research output: Contribution to journalArticle

Lu, Le ; Yoshimoto, Keiko ; Morita, Atsuho ; Kameda, Hideto ; Takeuchi, Tsutomu. / Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation. In: International Immunopharmacology. 2016 ; Vol. 39. pp. 273-279.
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