Elmlinger M W, Sanatani M S, Bell M, Dannecker G E, Ranke M B
Paediatric Endocrinology, University Children's Hospital, Tuebingen, Germany.
Eur J Endocrinol. 1998 Mar;138(3):337-43. doi: 10.1530/eje.0.1380337.
We recently found evidence indicating that the source of elevated serum insulin-like growth factor binding protein (IGFBP)-2 in leukemia was the leukemic T-cells. Here we report that locally produced IGF-II affects IGFBP-2 expression and growth of leukemic cells through the IGF type I receptor. We measured IGFBP-2, -4 and IGF type I receptor (IGF-I-R) mRNA by RT-PCR, cell growth and IGFBP-2 secretion (per 10(6) cells). IGF-I-R binding sites were assessed by 125I-IGF replacement studies. Inhibition using an IGF-II antibody showed that tumor cell-derived IGF-II accounts for a significant 25% (P < 0.001) increase in IGFBP-2 secretion and enhanced growth (P < 0.01) of leukemic T-cells after 7 days in culture. IGFBP-2 secretion, but not IGFBP-2 mRNA was specifically increased by IGFs, while no specific effect of insulin was detectable. The addition of 100 ng/ml IGF-II enhanced the IGFBP-2 secretion 2.8-fold, while the use of IGF-I only enhanced IGFBP-2 secretion 1.7-fold, although IGF-I enhanced IGF-II action. Through inhibition using JB1, a peptide inhibiting the IGF signal transduction by blocking the IGF-I-R, we demonstrated the involvement of the IGF-I-R in IGFBP-2 and -4 expression and leukemic cell growth. However, only slight differences in the IGF-I-R mRNA expression were seen for T- and B-cells compared with the differences found for the IGFBP-2 and -4 mRNA or IGFBP-2 secretion. Thus, although IGF-I-R mediates the autocrine/paracrine effects of the IGFs, IGF-I-R mRNA expression is most probably not involved in the differential IGFBP-2/IGFBP-4 expression in leukemic cells.
我们最近发现证据表明，白血病患者血清中胰岛素样生长因子结合蛋白（IGFBP）-2升高的来源是白血病T细胞。在此我们报告，局部产生的IGF-II通过IGF I型受体影响IGFBP-2的表达和白血病细胞的生长。我们通过逆转录聚合酶链反应（RT-PCR）检测IGFBP-2、-4和IGF I型受体（IGF-I-R）mRNA、细胞生长情况以及IGFBP-2分泌量（每10^6个细胞）。通过125I-IGF置换研究评估IGF-I-R结合位点。使用IGF-II抗体进行抑制实验表明，肿瘤细胞来源的IGF-II在培养7天后可使白血病T细胞的IGFBP-2分泌量显著增加25%（P<0.001），并促进其生长（P<0.01）。IGFs可特异性增加IGFBP-2的分泌，但不影响IGFBP-2 mRNA，而胰岛素未检测到特异性作用。添加100 ng/ml IGF-II可使IGFBP-2分泌量增加2.8倍，而使用IGF-I仅使其增加1.7倍，尽管IGF-I可增强IGF-II的作用。通过使用JB1（一种通过阻断IGF-I-R抑制IGF信号转导的肽）进行抑制实验，我们证明了IGF-I-R参与IGFBP-2和-4的表达以及白血病细胞的生长。然而，与IGFBP-2和-4 mRNA或IGFBP-2分泌量的差异相比，T细胞和B细胞在IGF-I-R mRNA表达上仅存在轻微差异。因此，尽管IGF-I-R介导IGFs的自分泌/旁分泌作用，但IGF-I-R mRNA表达很可能与白血病细胞中IGFBP-2/IGFBP-4的差异表达无关。
