title: Bortezomib regulates the chemotactic characteristics of T cells through downregulation of CXCR3/CXCL9 expression and induction of apoptosis.
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.
authors.affiliation: Department of Hematology, Peking University First Hospital, Xishiku Street, Beijing, 100034, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Han-Yun
authors.initials: HY
authors.lastname: Ren
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Dong
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Yin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Qiu
authors.forename: Xi-Nan
authors.initials: XN
authors.lastname: Cen
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Shi
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000502:physiology; D054370:Chemokine CXCL9 / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects*; D003864:Depression, Chemical; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D006086:Graft vs Host Disease / Q000188:drug therapy; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D011719:Pyrazines / Q000494:pharmacology*; D054400:Receptors, CCR7 / Q000096:biosynthesis / Q000235:genetics; D054367:Receptors, CXCR3 / Q000096:biosynthesis* / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001897:Boronic Acids; C515460:CCL19 protein, human; C515370:CCR7 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054415:Chemokine CCL19; D054370:Chemokine CXCL9; D011480:Protease Inhibitors; D011719:Pyrazines; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D000069286:Bortezomib; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1