Kayed H, Kleeff J, Keleg S, Büchler M W, Friess H
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
J Endocrinol. 2003 Sep;178(3):467-78. doi: 10.1677/joe.0.1780467.
Indian hedgehog (IHH) and its receptors patched (PTC) and smoothened (SMO) belong to the hedgehog family of signaling molecules, which are essential for a variety of patterning events during mammalian tIssue development. IHH plays a role in pancreas organogenesis and differentiation, as well as in the regulation of insulin production. In the present study, the expression of IHH and its receptors was analyzed in normal human pancreatic and chronic pancreatitis (CP) tIssues using Northern blotting, immunohistochemistry and Western blotting, and was correlated with clinicopathological parameters. In addition, the effects of inhibition and stimulation of the hedgehog signaling pathway on cell growth were determined in TAKA-1 normal pancreatic ductal cells. IHH mRNA was expressed in the normal human pancreas and CP tIssues, with slightly higher expression levels in CP. Using immunohistochemistry, IHH and its receptors were localized mainly in the islet cells of the normal pancreas. In CP, IHH and its receptors were present in the cells forming tubular complexes and in the islets with a different signal pattern compared with the islets in the normal pancreas. Correlation between diabetic and non-diabetic CP patients revealed no significant difference in IHH, SMO, or PTC immunoreactivity. Inhibition of hedgehog signaling in TAKA-1 pancreatic ductal cells using cyclopamine significantly reduced their growth through cell cycle arrest, while stimulation of the IHH pathway enhanced the growth of these cells. In conclusion, IHH and its receptors are expressed in the normal human pancreas and in CP, yet with a different distribution and cellular localization. IHH signaling may be involved in the pathogenesis of CP, i.e. in the formation and proliferation of tubular complexes and in islet cell dysfunction.
印度刺猬因子（IHH）及其受体patched（PTC）和smoothened（SMO）属于刺猬信号分子家族，它们在哺乳动物组织发育过程中的各种模式形成事件中至关重要。IHH在胰腺器官发生和分化以及胰岛素分泌调节中发挥作用。在本研究中，运用Northern印迹法、免疫组织化学和Western印迹法分析了IHH及其受体在正常人胰腺组织和慢性胰腺炎（CP）组织中的表达情况，并与临床病理参数进行关联分析。此外，还在TAKA-1正常胰腺导管细胞中测定了刺猬信号通路抑制和刺激对细胞生长的影响。IHH mRNA在正常人胰腺组织和CP组织中均有表达，在CP组织中的表达水平略高。运用免疫组织化学方法发现，IHH及其受体主要定位于正常胰腺的胰岛细胞中。在CP组织中，IHH及其受体存在于形成管状复合体的细胞以及胰岛中，与正常胰腺中的胰岛相比，其信号模式有所不同。糖尿病和非糖尿病CP患者之间的相关性分析显示，IHH、SMO或PTC免疫反应性无显著差异。使用环杷明抑制TAKA-1胰腺导管细胞中的刺猬信号通路可通过细胞周期阻滞显著降低其生长，而刺激IHH通路则可促进这些细胞的生长。总之，IHH及其受体在正常人胰腺组织和CP组织中均有表达，但分布和细胞定位不同。IHH信号通路可能参与CP的发病机制，即参与管状复合体的形成和增殖以及胰岛细胞功能障碍。
