Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells
Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells
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DOI：
10.1152/ajpgi.00413.2004
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发表时间：
2005-08-01
影响因子：
4.5
通讯作者：
Lund, PK
中科院分区：
文献类型：
--
作者：
Fruchtman, S;Simmons, JG;Lund, PK
细胞因子信号转导 2 的抑制剂可调节肠间充质细胞中 GH 和 IGF-I 的纤维化作用。 Am J Physiol Gastrointest Liver Physiol 289：G342-G350，2005。首次发表于 2005 年 4 月 14 日； doi:10.1152/ajpgi.00413.2004.-生长激素 (GH) 和 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 可能会诱导过度的胶原沉积，从而导致肠道纤维化。决定正常伤口愈合和过度愈合反应之间平衡的因素尚不清楚。使用 RNase 保护测定和原位杂交，我们确定了 GH 和/或 IGF-I 是否会增加全肠外营养 (TPN) 喂养大鼠肠道中的 I 型胶原沉积，TPN 是一种用于许多肠道手术和切除术后患者的喂养方式。我们还使用体外模型系统来确认我们的体内效果，并直接评估 GH 和 IGF-I 对肠道肌成纤维细胞 DNA 合成和胶原沉积的相对效力。 GH 和 IGF-I 均可在体内和体外刺激胶原蛋白的产生，并且 IGF-I（而非 GH）在体外刺激 DNA 合成。在胶原蛋白生成方面，GH 的效力不如 IGF-I。细胞因子信号传导抑制剂 (SOC) 是细胞因子诱导蛋白，可负反馈抑制细胞因子的作用，我们最近发现 GH 选择性上调 TPN 喂养大鼠肠道中的 SOC-2。我们研究了 SOC-2 是否可能导致 GH 和 IGF-I 对胶原蛋白积累作用程度的差异。 GH（而非 IGF-I）在分离的肌成纤维细胞中诱导 SOC-2，并且 SOC-2 的过度表达导致 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，注射 IGF-I 的 SOC-2 缺失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 无效小鼠中分离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 GH 或 GH 诱导的 IGF-I 诱导的胶原蛋白积累和间充质细胞增殖中发挥重要作用，为 GH 和 IGF-I 对肠间充质和胶原蛋白合成的不同效力提供了机制。
Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells. Am J Physiol Gastrointest Liver Physiol 289: G342-G350, 2005. First published April 14, 2005; doi:10.1152/ajpgi.00413.2004.-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. Myo-fibroblasts 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.