Original Article

International Journal of Hematology

, Volume 96, Issue 6, pp 764-772

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

  • Wei LiuAffiliated withDepartment of Hematology, Peking University First Hospital
  • , Han-Yun RenAffiliated withDepartment of Hematology, Peking University First Hospital Email author 
  • , Yu-Jun DongAffiliated withDepartment of Hematology, Peking University First Hospital
  • , Li-Hong WangAffiliated withDepartment of Hematology, Peking University First Hospital
  • , Yue YinAffiliated withDepartment of Hematology, Peking University First Hospital
  • , Yuan LiAffiliated withDepartment of Hematology, Peking University First Hospital
  • , Zhi-Xiang QiuAffiliated withDepartment of Hematology, Peking University First Hospital
  • , Xi-Nan CenAffiliated withDepartment of Hematology, Peking University First Hospital
  • , Yong-Jin ShiAffiliated withDepartment of Hematology, Peking University First Hospital

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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