International Journal of Hematology

, Volume 96, Issue 6, pp 764–772 | Cite as

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

  • Wei Liu
  • Han-Yun Ren
  • Yu-Jun Dong
  • Li-Hong Wang
  • Yue Yin
  • Yuan Li
  • Zhi-Xiang Qiu
  • Xi-Nan Cen
  • Yong-Jin Shi
Original Article

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.

Keywords

Bortezomib T lymphocyte Chemokine Chemokine receptor Apoptosis 

Notes

Acknowledgments

We thank Dr. Pei Pei and Dr. Hong-Jun Hao for their technical support. This work was supported by grants from the National Natural Science Foundation of China (No. 30940030 & 81070448) and China National Key Technology R&D Program (No. 2008BAI61B01).

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© The Japanese Society of Hematology 2012

Authors and Affiliations

  • Wei Liu
    • 1
  • Han-Yun Ren
    • 1
  • Yu-Jun Dong
    • 1
  • Li-Hong Wang
    • 1
  • Yue Yin
    • 1
  • Yuan Li
    • 1
  • Zhi-Xiang Qiu
    • 1
  • Xi-Nan Cen
    • 1
  • Yong-Jin Shi
    • 1
  1. 1.Department of HematologyPeking University First HospitalBeijingChina

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