Cooper S, Mantel C, Broxmeyer H E
Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, Indianapolis 46202-5121.
Exp Hematol. 1994 Feb;22(2):186-93.
Macrophage inflammatory protein (MIP)-1 alpha has myelosuppressive/myeloprotective effects in vivo in mice. We recently reported that > 99.7% of recombinant murine (rm) MIP-1 alpha polymerizes rapidly at relatively high concentrations in physiological salt solution, and it is the monomeric form of MIP-1 alpha that is active in vitro as a myelosuppressive factor. Polymerized MIP-1 alpha is inactive in this effect and does not block the myelosuppressive action of monomeric MIP-1 alpha. MIP-1 alpha could be maintained in monomeric form in physiological saline if diluted to low concentrations. This led us to reevaluate the actual amounts of MIP-1 alpha necessary for myelosuppression in vivo. C3H/HeJ mice were injected intravenously (i.v.) with monomeric rmMIP-1 alpha or control diluent and effects were evaluated on progenitor cells--multipotent colony-forming units (CFU-GEMM), burst-forming units-erythroid (BFU-E), and colony-forming units-granulocyte/macrophage (CFU-GM)--as described in previous studies in which MIP-1 alpha concentrations were used that we now know to have been mainly in polymerized form. Monomeric MIP-1 alpha rapidly decreased cycling rates and absolute numbers of myeloid progenitor cells in marrow and spleen. These effects, which occurred with about 1000-fold less MIP-1 alpha than we previously reported, were dose-dependent, time-related, and reversible. Suppressive effects were noted within 3 hours for cell cycling and within 24 hours for absolute numbers of progenitor cells in marrow and spleen and were lost by 48 hours. Decreased circulating neutrophils were noted at 48 hours. Column-separated polymerized rmMIP-1 alpha was inactive in vivo. These results demonstrate the potency of low doses of monomeric MIP-1 alpha in vivo. Since clinical administration of large amounts of an agent that is mainly in an inactive form may result in severe pharmacological side effects, the information presented here is of relevance for potential clinical trials using MIP-1 alpha as a myelosuppressive/myeloprotective agent.
巨噬细胞炎性蛋白（MIP）-1α在小鼠体内具有骨髓抑制/骨髓保护作用。我们最近报道，在生理盐溶液中，超过99.7%的重组鼠（rm）MIP-1α在相对高浓度下会迅速聚合，而作为骨髓抑制因子在体外具有活性的是MIP-1α的单体形式。聚合的MIP-1α在这种作用中无活性，且不会阻断单体MIP-1α的骨髓抑制作用。如果稀释至低浓度，MIP-1α可以在生理盐水中保持单体形式。这使我们重新评估了体内骨髓抑制所需的MIP-1α的实际量。将单体rmMIP-1α或对照稀释剂静脉内（i.v.）注射到C3H/HeJ小鼠体内，并如先前研究中那样评估对祖细胞——多能集落形成单位（CFU-GEMM）、红系爆式集落形成单位（BFU-E）和粒细胞/巨噬细胞集落形成单位（CFU-GM）——的影响，在先前研究中使用的MIP-1α浓度我们现在知道主要是聚合形式。单体MIP-1α迅速降低了骨髓和脾脏中髓系祖细胞的循环速率和绝对数量。这些效应在所需的MIP-1α量比我们先前报道的少约1000倍的情况下出现，具有剂量依赖性、时间相关性且是可逆性的。在3小时内观察到对细胞循环的抑制作用，在24小时内观察到对骨髓和脾脏中祖细胞绝对数量的抑制作用，并且在48小时时这种抑制作用消失。在48小时时观察到循环中性粒细胞减少。经柱分离的聚合rmMIP-1α在体内无活性。这些结果证明了低剂量单体MIP-1α在体内的效力。由于临床给予主要以无活性形式存在的大量药物可能会导致严重的药理学副作用，此处提供的信息对于使用MIP-1α作为骨髓抑制/骨髓保护剂的潜在临床试验具有相关性。
