Shibakura Misako, Niiya Kenji, Niiya Masami, Asaumi Noboru, Yoshida Chikamasa, Nakata Yasunari, Tanimoto Mitsune
Department of Medical Technology, Faculty of Health Sciences, Okayama University Medical School, Okayama 700-8558, Japan.
Leuk Res. 2005 Jul;29(7):755-9. doi: 10.1016/j.leukres.2005.01.005. Epub 2005 Feb 26.
We previously reported the induction of interleukin-8 (IL-8), one of the CXC chemokines, by all-trans retinoic acid (ATRA) in PL-21 and NB4 human myeloid leukemia cells, which may be implicated in APL differentiation syndrome that is a relatively frequent complication in patients with acute promyelocytic leukemia (APL) during treatment with ATRA. We, therefore, further investigated the effects of ATRA on the expression of chemokine family in NB4 cells and APL cells prepared from two APL patients. The RNase protection assay using a multi-probe template set for human chemokines revealed that ATRA induced gene expressions of a number of CC chemokines, such as monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in NB4 cells. Their antigen levels were also increased in the cultured media. APL cells prepared from two APL patients showed gene expression of chemokines, such as IL-8, MCP-1, MIP-1alpha, and MIP-1beta when stimulated with ATRA in vitro. Furthermore, serum levels of IL-8, MIP-1beta and RANTES were increased during the course of ATRA treatment in both APL patients who developed APL differentiation syndrome. These chemokines are all chemoattractants of particular inflammatory cell types, including neutrophils, monocytes and lymphocytes; therefore, the simultaneous induction of these chemokines after stimulation with ATRA may exacerbate the hyper-inflammation observed in ATRA-induced APL differentiation syndrome.
我们之前报道过，全反式维甲酸（ATRA）可在PL - 21和NB4人髓系白血病细胞中诱导CXC趋化因子之一的白细胞介素 - 8（IL - 8）表达，这可能与急性早幼粒细胞白血病（APL）分化综合征有关，该综合征是APL患者在接受ATRA治疗期间相对常见的并发症。因此，我们进一步研究了ATRA对NB4细胞以及从两名APL患者制备的APL细胞中趋化因子家族表达的影响。使用针对人趋化因子的多探针模板集进行的核糖核酸酶保护分析表明，ATRA可诱导NB4细胞中多种CC趋化因子的基因表达，如单核细胞趋化蛋白 - 1（MCP - 1）、巨噬细胞炎性蛋白（MIP）-1α和MIP - 1β。它们在培养基中的抗原水平也有所增加。从两名APL患者制备的APL细胞在体外经ATRA刺激后，显示出趋化因子如IL - 8、MCP - 1、MIP - 1α和MIP - 1β的基因表达。此外，在发生APL分化综合征的两名APL患者接受ATRA治疗过程中，血清中IL - 8、MIP - 1β和调节激活正常T细胞表达和分泌因子（RANTES）水平升高。这些趋化因子都是特定炎症细胞类型（包括中性粒细胞、单核细胞和淋巴细胞）的趋化剂；因此，ATRA刺激后同时诱导这些趋化因子可能会加剧在ATRA诱导的APL分化综合征中观察到的过度炎症反应。
