De Benedetti F, Meazza C, Martini A
Pediatria Generale e Reumatologia, IRCCS Policlinico San Matteo, Pavia, Italia.
Horm Res. 2002;58 Suppl 1:24-7. doi: 10.1159/000064757.
Indirect evidence suggests a link between factors produced during the inflammatory response and stunted growth. The demonstration of this link was provided by the observation that mice transgenic for the inflammatory cytokine interleukin-6 (IL-6), expressing high circulating levels of IL-6 since birth, show a marked decrease in growth rate leading to adult mice 50-70% the size of wild-type littermates. The growth defect is completely abolished by neutralization of IL-6. In these mice the production of GH is normal, while circulating levels of IGF-I are markedly decreased. Administration of IL-6 to wild-type mice results in a marked decrease in IGF-I levels. These observations show that in vivo high levels of IL-6 are associated with low levels of IGF-I. However, IL-6 does not directly affect IGF-I production both in vitro and in vivo. In contrast, markedly decreased levels of IGFBP-3 are present in the IL-6 transgenic mice and administration of IL-6 to wild-type mice results in a marked decrease in IGFBP-3 levels. In these mice the decrease in IGFBP-3 levels is associated with impaired formation of the 150 kD ternary complex, even in the presence of normally functional ALS. As a consequence, IL-6 transgenic mice show increased clearance of circulating IGF-I, suggesting that IL-6 decreases IGF-I levels by increased clearance. Proteolytic degradation of IGFBP-3 occurs in the IL-6 transgenic mice, suggesting that the decrease in IGFBP-3 could be at least in part due to proteolysis. The abnormalities of the IGF-I system observed in the IL-6 transgenic mice are similar to those found in patients with systemic juvenile idiopathic arthritis, one of the chronic inflammatory diseases characterized by stunted growth and prominent production of IL-6. The IL-6 transgenic mice represent a faithful animal model of the growth impairment associated with chronic inflammation and may therefore provide information relevant to the understanding and treatment of this complication of inflammatory diseases.
间接证据表明炎症反应过程中产生的因子与生长发育迟缓之间存在联系。这种联系是通过以下观察得到证实的：携带炎症细胞因子白细胞介素-6（IL-6）转基因的小鼠自出生起循环中IL-6水平就很高，其生长速率显著下降，成年小鼠体型仅为野生型同窝小鼠的50%-70%。通过中和IL-6，生长缺陷完全消除。在这些小鼠中，生长激素（GH）的产生正常，而胰岛素样生长因子-I（IGF-I）的循环水平显著降低。给野生型小鼠注射IL-6会导致IGF-I水平显著下降。这些观察结果表明，体内高水平的IL-6与低水平的IGF-I相关。然而，IL-6在体外和体内均不直接影响IGF-I的产生。相反，IL-6转基因小鼠中胰岛素样生长因子结合蛋白-3（IGFBP-3）水平显著降低，给野生型小鼠注射IL-6也会导致IGFBP-3水平显著下降。在这些小鼠中，即使存在正常功能的酸性不稳定亚基（ALS），IGFBP-3水平的降低也与150kD三元复合物形成受损有关。因此，IL-6转基因小鼠循环中IGF-I的清除增加，提示IL-6通过增加清除来降低IGF-I水平。IGFBP-3在IL-6转基因小鼠中发生蛋白水解降解，提示IGFBP-3的降低至少部分归因于蛋白水解。在IL-6转基因小鼠中观察到的IGF-I系统异常与系统性幼年特发性关节炎患者相似，系统性幼年特发性关节炎是一种以生长发育迟缓以及IL-6大量产生为特征的慢性炎症性疾病。IL-6转基因小鼠代表了与慢性炎症相关的生长障碍的可靠动物模型，因此可能为理解和治疗炎症性疾病的这种并发症提供相关信息。
