Fruchtman Shira, Simmons James G, Michaylira Carmen Z, Miller Megan E, Greenhalgh Christopher J, Ney Denise M, Lund P Kay
Dept. of Cell and Molecular Physiology, CB#7545, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599-7545, USA.
Am J Physiol Gastrointest Liver Physiol. 2005 Aug;289(2):G342-50. doi: 10.1152/ajpgi.00413.2004. Epub 2005 Apr 14.
Growth hormone (GH) and IGF-I play important roles in wound healing during intestinal injury and inflammation, but there is also indirect evidence that locally expressed IGF-I may act to induce excessive collagen deposition, which can lead to intestinal fibrosis. Factors that dictate the balance between normal wound healing and excessive healing responses are unknown. Using RNase protection assay and in situ hybridization, we determined whether GH and/or IGF-I increase type I collagen deposition in the intestine of rats fed by total parenteral nutrition (TPN), a feeding modality used for many patients following intestinal surgery and resection. We also used an in vitro model system to confirm our in vivo effects and to directly evaluate the relative potency of GH and IGF-I on DNA synthesis and collagen deposition in intestinal myofibroblasts. Both GH and IGF-I stimulated collagen production in vivo and in vitro, and IGF-I, but not GH, stimulated DNA synthesis in vitro. In collagen production, GH was less potent than IGF-I. Suppressors of cytokine signaling (SOC) are cytokine-inducible proteins that negatively feedback to inhibit the actions of cytokines and we recently found that GH selectively upregulates SOC-2 in the intestine of TPN-fed rats. We examined whether SOC-2 may be responsible for the difference in magnitude of action of GH and IGF-I on collagen accumulation. GH, but not IGF-I, induced SOC-2 in isolated myofibroblasts, and overexpression of SOC-2 led to a suppression of GH- and IGF-I-induced collagen accumulation. SOC-2 null mice infused with IGF-I showed greater collagen gene expression compared with wild-type (WT) mice. Myofibroblasts isolated from SOC-2 null mice showed increased IGF-I-stimulated DNA synthesis compared with WT cells. Taken together, these findings suggest that SOC-2 induced by GH may play an important role in suppressing collagen accumulation and mesenchymal cell proliferation induced by GH or GH-induced IGF-I, providing a mechanism for the differing potencies of GH and IGF-I on intestinal mesenchyme and collagen synthesis.
生长激素（GH）和胰岛素样生长因子-I（IGF-I）在肠道损伤和炎症期间的伤口愈合中发挥重要作用，但也有间接证据表明局部表达的IGF-I可能会促使胶原蛋白过度沉积，进而导致肠道纤维化。决定正常伤口愈合与过度愈合反应之间平衡的因素尚不清楚。我们运用核糖核酸酶保护分析和原位杂交技术，来确定GH和/或IGF-I是否会增加接受全胃肠外营养（TPN）喂养的大鼠肠道中I型胶原蛋白的沉积。TPN是许多肠道手术和切除术后患者所采用的一种喂养方式。我们还使用了体外模型系统来证实体内实验结果，并直接评估GH和IGF-I对肠道肌成纤维细胞DNA合成和胶原蛋白沉积的相对效力。GH和IGF-I在体内和体外均能刺激胶原蛋白生成，且IGF-I（而非GH）在体外能刺激DNA合成。在胶原蛋白生成方面，GH的效力低于IGF-I。细胞因子信号转导抑制因子（SOC）是细胞因子诱导的蛋白质，可通过负反馈抑制细胞因子的作用，我们最近发现GH能选择性地上调接受TPN喂养大鼠肠道中的SOC-2。我们研究了SOC-2是否可能是导致GH和IGF-I对胶原蛋白积累作用强度差异的原因。GH（而非IGF-I）能在分离出的肌成纤维细胞中诱导SOC-2表达，且SOC-2的过表达会导致GH和IGF-I诱导的胶原蛋白积累受到抑制。与野生型（WT）小鼠相比，注入IGF-I的SOC-2基因敲除小鼠表现出更高的胶原蛋白基因表达。与WT细胞相比，从SOC-2基因敲除小鼠分离出的肌成纤维细胞显示出IGF-I刺激的DNA合成增加。综上所述，这些发现表明GH诱导的SOC-2可能在抑制由GH或GH诱导的IGF-I所引起的胶原蛋白积累和间充质细胞增殖方面发挥重要作用，这为GH和IGF-I在肠道间充质和胶原蛋白合成方面的不同效力提供了一种机制。
