Proietti E, Tritarelli E, Gabriele L, Testa U, Greco G, Pelosi E, Gabbianelli M, Belardelli F, Peschle C
Department of Virology, Istituto Superiore di Sanità, Rome, Italy.
Cancer Res. 1993 Feb 1;53(3):569-76.
We have studied the effects of single and combined treatment with interleukin 1 beta (IL-1 beta) and interleukin 2 (IL-2) on spleen and bone marrow hematopoiesis in normal mice. Injection of IL-1 beta alone was followed by a significant increase in the number of granulocytes in spleen and progenitors (burst-forming units-erythroid and colony-forming units-granulomonocytic) in both spleen and bone marrow, s compared to control mice. In contrast, IL-2 alone induced only a slight increase in the number of marrow colony-forming units-granulomonocytic and had no significant effect on spleen progenitors. Repeated injections of both IL-1 beta and IL-2 resulted in a synergistic increase in spleen weight and splenocyte number, as compared to mice treated with the single cytokine regimen; in particular, the combined treatment induced a marked rise in the number of neutrophilic granulocytes and erythroblasts, whereas splenic lymphocytes were not affected. This regimen also caused a synergistic increase in the number of spleen and marrow progenitor cells: a time-course analysis showed an elevation in numbers of both burst-forming units-erythroid and colony-forming units-granulomonocytic, first in marrow (day 10) and subsequently in spleen (day 18). Combined IL-1 beta/IL-2 treatment dampened the decrease and accelerated the recovery of myeloid cells after cyclophosphamide injection, whereas the single cytokine regimen was not effective. Similarly, the rebound of WBC (especially neutrophilic granulocytes) after cyclophosphamide treatment was markedly enhanced by the combined treatment, whereas the single cytokine regimen was ineffective. These results, indicating a myelostimulatory effect by the combined cytokine regimen, together with our previous observations showing a synergistic antitumor activity by IL-1/IL-2 treatment in experimental mouse tumors (V. Ciolli et al., J. Exp. Med., 173: 313-322, 1991), may provide the basis for the development of new combination therapies with cytokines and antiblastic agents in the treatment of cancer patients.
我们研究了白细胞介素1β（IL-1β）和白细胞介素2（IL-2）单独及联合处理对正常小鼠脾脏和骨髓造血功能的影响。与对照小鼠相比，单独注射IL-1β后，脾脏中粒细胞数量以及脾脏和骨髓中的祖细胞（红细胞爆式集落形成单位和粒单系集落形成单位）显著增加。相比之下，单独使用IL-2仅使骨髓粒单系集落形成单位数量略有增加，对脾脏祖细胞无显著影响。与用单一细胞因子方案处理的小鼠相比，重复注射IL-1β和IL-2导致脾脏重量和脾细胞数量协同增加；特别是联合处理使嗜中性粒细胞和红细胞数量显著增加，而脾淋巴细胞未受影响。该方案还使脾脏和骨髓祖细胞数量协同增加：时间进程分析显示，红细胞爆式集落形成单位和粒单系集落形成单位数量均先在骨髓中升高（第10天），随后在脾脏中升高（第18天）。联合IL-1β/IL-2处理减轻了环磷酰胺注射后骨髓细胞的减少并加速了其恢复，而单一细胞因子方案无效。同样，联合处理显著增强了环磷酰胺处理后白细胞（尤其是嗜中性粒细胞）的反弹，而单一细胞因子方案无效。这些结果表明联合细胞因子方案具有骨髓刺激作用，连同我们之前观察到的IL-1/IL-2处理在实验性小鼠肿瘤中具有协同抗肿瘤活性（V. Ciolli等人，《实验医学杂志》，173: 313 - 322，1991），可能为开发细胞因子与抗有丝分裂药物联合治疗癌症患者的新疗法提供基础。
