Growth hormone inhibits signal transducer and activator of transcription 3 activation and reduces disease activity in murine colitis
Growth hormone inhibits signal transducer and activator of transcription 3 activation and reduces disease activity in murine colitis
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DOI：
10.1053/j.gastro.2005.05.018
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发表时间：
2005-07-01
期刊：
影响因子：
29.4
通讯作者：
Denson, LA
中科院分区：
文献类型：
--
作者：
Han, XN;Sosnowska, D;Denson, LA
背景和目标：组成性信号转导和转录激活因子（STAT）3激活促进小鼠结肠炎和人类炎症性肠病的慢性炎症和上皮细胞增殖。SHP-2通过与糖蛋白130信号受体结合，负调节STAT 3激活。生长激素可减少疾病活动，促进结肠炎粘膜愈合，并可激活SHP-2。研究方法：我们假设，生长激素的管理将减少疾病的活动，在实验性结肠炎，这将涉及SHP-2/糖蛋白130协会和STAT 3激活的调制。结果：生长激素治疗改善了白细胞介素10基因敲除小鼠结肠炎的体重增加和结肠组织学。生长激素可减少隐窝上皮细胞的凋亡，增加其增殖，同时增加固有层单核细胞的凋亡。生长激素增加了SHP-2/糖蛋白130的结合，减少了白细胞介素10缺失小鼠和克罗恩氏结肠炎患者活检样本中结肠STAT 3的激活。抗凋亡蛋白bcl-2的表达增加后，生长激素治疗的隐窝上皮细胞。在T84人结肠癌和Jurkat人T细胞白血病细胞系中，生长激素增加SHP-2/糖蛋白130结合并减少白细胞介素6依赖性STAT 3活化。结论：给予生长激素可改善白细胞介素10缺失结肠炎小鼠的体重增加并降低疾病活动性。疾病活动性的改善与鼠结肠炎和克罗恩氏结肠炎中SHP-2/糖蛋白130结合增加和STAT 3活化减少相关。生长激素可能是一种有用的治疗炎症性肠病，在改善合成代谢和促进粘膜愈合方面。
Background & Aims: Constitutive signal transducer and activator of transcription (STAT) 3 activation promotes chronic inflammation and epithelial proliferation in murine colitis and human inflammatory bowel disease. SHP-2, through binding to the glycoprotein 130 signaling receptor, negatively regulates STAT3 activation. Growth hormone reduces disease activity and promotes mucosal healing in colitis and can activate SHP-2. Methods: We hypothesized that growth hormone administration would reduce disease activity in experimental colitis and that this would involve modulation of SHP-2/glycoprotein 130 association and STAT3 activation. Results: Growth hormone administration improved weight gain and colon histology in interleukin 10-null mice with colitis. Growth hormone reduced apoptosis and increased proliferation of crypt epithelial cells while increasing apoptosis of lamina propria mononuclear cells. Growth hormone increased SHP-2/glycoprotein 130 association and reduced colonic STAT3 activation in interleukin 10-null mice and in biopsy samples from patients with Crohn's colitis. Expression of the antiapoptotic protein bcl-2 was increased in crypt epithelial cells after growth hormone treatment. Growth hormone increased SHP-2/glycoprotein 130 binding and reduced interleukin 6-dependent STAT3 activation in the T84 human colon carcinoma and Jurkat human T-cell leukemia lines. Conclusions: Growth hormone administration improves weight gain and reduces disease activity in interleukin 10-null mice with colitis. The improvement in disease activity is associated with increased SHP-2/glycoprotein 130 binding and reduced STAT3 activation in both murine and Crohn's colitis. Growth hormone may be a useful therapy in inflammatory bowel disease, in terms of both improving anabolic metabolism and enhancing mucosal healing.