A۲۰ inhibits doxorubicin-induced macrophage maturation and apoptosis through mTOR signaling in classical Hodgkin lymphoma

Objective(s): Classical Hodgkin lymphoma (cHL) is identified by the appearance of Hodgkin and Reed-Sternberg cells. A۲۰ and CYLD are deubiquitinating enzymes involved in negatively regulating NF-κB-mediated immune response. Vincristine (Vinc) and doxorubicin (Dox) are classical antitumor drugs, in which Dox serves a key role in chemotherapy against cHL and Vinc induces disruption of microtubule function that inhibits mitosis of cancer cells. Little is known about the roles of A۲۰/CYLD in regulating macrophage function from cHL patients upon treatment with Vinc or Dox. This study, therefore, asked whether A۲۰/CYLD expression affects function of macrophages in cHL cases. Materials and Methods: Macrophages from cHL patients differentiated from bone marrow cells were exposed to Vinc or Dox. Gene expression levels were determined by real time-qPCR, cell maturation, apoptosis and phagocytosis by flow cytometry, and cytokine release by ELISA. Results: Dox induced maturation, apoptosis, and phagocytosis of macrophages in cHL cases. Moreover, the percentage of CD۶۸+CD۴۰+, but not CD۶۸+CD۸۶+ cells as well as levels of IL-۱β were further enhanced when exposed to A۲۰ siRNA, whereas the absence of CYLD unaltered macrophage function in cHL patients. Importantly, the increased numbers of A۲۰-sensitive CD۶۸+CD۴۰+ and Annexin V-PI+ cells as well as enhanced levels of caspase ۳ were abolished in the presence of mTOR inhibitor Everolimus. Conclusion: The present study indicates that Dox-induced macrophage maturation and apoptosis are dependent on A۲۰ expression through mTOR signaling. Moreover, inhibition of Dox-induced macrophage maturation in the patients with low A۲۰ expression by Everolimus might represent a promising therapy for A۲۰-sensitive cHL cases.

کلیدواژه ها:

A۲۰ ، Classical hodgkin lymphoma ، Everolimus ، IL-۱β ، Macrophages