Bortezomib regulates the chemotactic characteristics of T cells through downregulation of CXCR3/CXCL9 expression and induction of apoptosis

Int J Hematol. 2012 Dec;96(6):764-72. doi: 10.1007/s12185-012-1195-6. Epub 2012 Nov 23.

Abstract

The chemotactic movement of T lymphocytes mediated by chemokines and their receptors plays an important role in the pathogenesis of graft-versus-host disease (GVHD) post-allogeneic hematopoietic stem cell transplantation (allo-HSCT). CCR7 and CXCR3 are two receptors associated with the development of GVHD. Bortezomib, a proteasome inhibitor, was recently found to prevent GVHD in a mouse model and to decrease the production of Th1 cytokines. Here, we report that bortezomib differentially regulates the expression of CXCR3 and CCR7 on T cells; it significantly decreases CXCR3 expression on T cells as well as its CD4(+)/CD8(+) subsets in a dose-dependent manner, while it does not significantly affect CCR7 expression on T cells and subsets. Moreover, the secretion of CXCL9 by activated T cells is also increasingly downregulated with increasing concentrations of bortezomib. Meanwhile, bortezomib inhibits T-cell chemotactic movements toward CXCL9 in a dose-dependent manner, but has no effect on CCL19-induced T-cell chemotaxis. Additionally, it was found that bortezomib treatment also prompts T-lymphocyte apoptosis through activation of caspase-3 and its downstream PARP cleavage in a dose- and time-dependent manner. These results suggest that bortezomib may act as a suppressor of GVHD by downregulating T-cell chemotatic movement toward GVHD target organs, as well as by inducing apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apoptosis / drug effects*
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Cells, Cultured
  • Chemokine CCL19 / physiology
  • Chemokine CXCL9 / metabolism*
  • Chemotaxis / drug effects*
  • Depression, Chemical
  • Down-Regulation
  • Drug Evaluation, Preclinical
  • Graft vs Host Disease / drug therapy
  • Humans
  • Lymphocyte Activation / drug effects
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Phosphorylation
  • Protease Inhibitors / pharmacology*
  • Protein Processing, Post-Translational
  • Pyrazines / pharmacology*
  • Receptors, CCR7 / biosynthesis
  • Receptors, CCR7 / genetics
  • Receptors, CXCR3 / biosynthesis*
  • Receptors, CXCR3 / genetics
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocyte Subsets / metabolism

Substances

  • Boronic Acids
  • CCL19 protein, human
  • CCR7 protein, human
  • CXCL9 protein, human
  • CXCR3 protein, human
  • Chemokine CCL19
  • Chemokine CXCL9
  • Protease Inhibitors
  • Pyrazines
  • Receptors, CCR7
  • Receptors, CXCR3
  • Bortezomib
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1