Abstract
Blocking the CXCL12/CXCR4 axis can alter the biological functions of leukaemia cells. We hypothesise that interleukin (IL)-8 and IL-6 play an important role in this process. To test this hypothesis, we established a co-culture model of leukaemia cells and bone marrow stromal cells. Treatment of cells with AMD3100, a CXCR4 antagonist, and G-CSF blocked the CXCL12/CXCR4 axis, inducing biological changes in the leukaemia cells and altering IL-8 and IL-6 levels. Subsequently, after stimulating the CXCL12/CXCR4 axis, specific pathway blockers were employed to assess the role of four candidate signalling pathways in this process. ELISA results confirmed that MG-132 (10 μm) inhibits IL-8 expression and that the NF-κB signalling pathway contributes to this effect. Moreover, treatment with Perifosine, an AKT inhibitor, inhibited IL-6 expression. In addition, changes in the NF-κB signalling pathway inhibited IL-8 expression. Treatment with SP600125, a Jun N-terminal kinase inhibitor, and Perifosine also inhibited IL-8 expression; however, this effect occurred later. IL-6 expression was also lower in the Perifosine group; hence, inhibiting the PI3K/AKT signalling pathway can reduce IL-6 expression. This process requires the participation of multiple signalling pathways to regulate IL-8 and IL-6 expression. Therefore, the associated mechanism is likely to be highly intricate, with potential cross-effects that may impact leukaemia pathogenesis. IL-6 and IL-8 are physiologically regulated by the CXCL12/CXCR4 axis, while the NF-κB and JNK/AP-1 pathways are required for IL-8 expression in T-cell acute lymphoblastic leukaemia. Accordingly, by upregulating IL-8, the bone marrow microenvironment and CXCL12/CXCR4 axis may contribute to T-cell acute lymphoblastic leukaemia pathogenesis.
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The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The current study was supported by grants from Supporting Fund for Teachers’ research of Jining Medical University (grant no. JYFC2018FKJ027), the Science and technology development plan of Zhangqiu District in 2019 (grant no. 12), and the Science and technology development plan of Zhangqiu People’s Hospital of Jinan in 2018 (grant no. 2018ZY16).
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LZ and GQ contributed to the study design. LZ, HZ, and CZ performed the experiments. LZ prepared the manuscript and prepared figures , LZ GQ and CZperformed the statistical analysis and interpreted the data. DL contributed to the experimental design and paper writing. All authors reviewed the manuscript. All authors read and approved the final manuscript.
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Zhou, L., Zhao, H., Zhang, C. et al. Study on the mechanism of CXCL12/CXCR4-axis-mediated upregulation of IL-8 and IL-6 on the biological function of acute T lymphocyte leukaemia cells. Cytotechnology 76, 97–111 (2024). https://doi.org/10.1007/s10616-023-00600-3
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DOI: https://doi.org/10.1007/s10616-023-00600-3