Visani G, Tosi P, Ottaviani E, Zaccaria A, Baccini C, Manfroi S, Pastano R, Remiddi C, Morelli A, Molinari A L, Zanchini R, Tura S
Institute of Hematology and Medical Oncology, Seràgnoli, University of Bologna, Italy.
Eur J Haematol. 1996 Oct;57(4):301-6. doi: 10.1111/j.1600-0609.1996.tb01381.x.
Leukemic cells spontaneously secrete cytokines involved in the proliferation of the clone; in this study we evaluated the effects of all-trans retinoic acid (ATRA) on the in vitro autocrine production of cytokines by acute myeloid leukemia cells. Thirty acute nonlymphoid leukemia cases (ANLL) (10 APL and 20 ANLL of other cytotypes than APL) were studied; the in vitro secretions of IL-1 alpha, IL-3, IL-4, IL-6, IL-10, G-CSF, GM-CSF, TNF-alpha were tested with and without ATRA addition. After 5 d exposure to ATRA 10(-6) M APL-treated samples showed a significant reduction of IL-6 (p = 0.008) and GM-CSF (p = 0.03) and a significant increase of IL-1 alpha (p = 0.01) production, if compared to untreated APL samples. No difference was seen in IL-3, IL-10 and IL-4 productions; G-CSF production resulted absent in all but 3 APL cases, in which addition of ATRA determined increase in the production. Interestingly, the 3 G-CSF-producing cases did not obtain clinical remission with ATRA; GM-CSF and IL-6 were spontaneously produced by all the cases, and 7 of 10 APL patients subsequently obtained complete remission after induction. TNF-alpha was produced only in 1 case. No statistical difference was seen in all the productions obtained from other than promyelocytic acute leukemic cells, both with and without ATRA addition. However, it is noteworthy that the production of IL-6 was more than twice as high in ANLL non-APL than in APL cases. In conclusion, these data could thus suggest possible complementary mechanisms of the exhaustion of the leukemic clone upon treatment with ATRA.
白血病细胞可自发分泌参与克隆增殖的细胞因子；在本研究中，我们评估了全反式维甲酸（ATRA）对急性髓系白血病细胞体外自分泌细胞因子的影响。研究了30例急性非淋巴细胞白血病病例（ANLL）（10例急性早幼粒细胞白血病（APL）和20例非APL细胞类型的ANLL）；在添加和不添加ATRA的情况下，检测IL-1α、IL-3、IL-4、IL-6、IL-10、粒细胞集落刺激因子（G-CSF）、粒细胞-巨噬细胞集落刺激因子（GM-CSF）、肿瘤坏死因子-α（TNF-α）的体外分泌情况。与未处理的APL样本相比，用10⁻⁶ M ATRA处理5天后，APL样本中IL-6（p = 0.008）和GM-CSF（p = 0.03）显著减少，IL-1α产生显著增加（p = 0.01）。IL-3、IL-10和IL-4的产生未见差异；除3例APL病例外，所有病例均未检测到G-CSF产生，在这3例中添加ATRA后G-CSF产生增加。有趣的是，这3例产生G-CSF的病例未通过ATRA获得临床缓解；所有病例均自发产生GM-CSF和IL-6，10例APL患者中有7例在诱导后随后获得完全缓解。仅1例产生TNF-α。在添加和不添加ATRA的情况下，从早幼粒细胞性急性白血病细胞以外的其他细胞获得的所有产物均未观察到统计学差异。然而，值得注意的是，非APL的ANLL中IL-6的产生比APL病例高两倍多。总之，这些数据因此可能提示ATRA治疗后白血病克隆耗竭的可能互补机制。
