Alvaro Domenico, Metalli Veronica Drudi, Alpini Gianfranco, Onori Paolo, Franchitto Antonio, Barbaro Barbara, Glaser Shannon S, Francis Heather, Cantafora Alfredo, Blotta Ida, Attili Adolfo Francesco, Gaudio Eugenio
Division of Gastroenterology, University of Rome, La Sapienza, Rome, Italy.
J Hepatol. 2005 Nov;43(5):875-83. doi: 10.1016/j.jhep.2005.04.011. Epub 2005 May 31.
BACKGROUND/AIMS: We evaluated the role and mechanisms by which the GH/IGF1 axis modulates cholangiocyte proliferation.
GH-receptors (GH-R), IGF1, IGFBP3 (binding protein 3), IGF1-R and receptor substrates (IRS) were evaluated in cholangiocytes of normal or bile duct-ligated (BDL) rat livers. The effects of GH and IGF1 on proliferation of normal quiescent cholangiocytes and the transduction pathways involved were investigated.
IGF1, GH-R, IGF1-R, IRS-1/2 were expressed in normal cholangiocytes and overexpressed in cholangiocytes proliferating after BDL which also secrete IGF1 in a higher amount than normal cells. IGFBP3, which may counter-regulate IGF1 effects, was decreased in BDL cholangiocytes. IGF1 promoted cholangiocyte proliferation in association with overexpression of p-IGF1R, IRS1, IRS-2, p-ERK1/2 and p-AKT. GH induced IGF1 expression and release in isolated cholangiocytes, and reproduced the effects of IGF1 but GH effects were abolished by IGF1-R blocking antibody, suggesting IGF1 as a mediator of GH. Finally, IGF1 and 17beta-estradiol reciprocally potentiated their proliferative effects on cholangiocytes, and by interacting at both receptor and post-receptor levels.
Cholangiocytes respond to GH with production and release of IGF1 that modulates cell proliferation by transduction pathways involving IGF1-R, IRS1/2 and both ERK and PI3-kinase pathways. The biliary epithelium is a target of GH/IGF1 liver axis.
背景/目的：我们评估了生长激素/胰岛素样生长因子1（GH/IGF1）轴调节胆管细胞增殖的作用及机制。
在正常或胆管结扎（BDL）大鼠肝脏的胆管细胞中评估生长激素受体（GH-R）、IGF1、IGFBP3（结合蛋白3）、IGF1受体（IGF1-R）和受体底物（IRS）。研究了GH和IGF1对正常静止胆管细胞增殖的影响以及相关的转导途径。
IGF1、GH-R、IGF1-R、IRS-1/2在正常胆管细胞中表达，并在BDL后增殖的胆管细胞中过表达，这些增殖的胆管细胞分泌的IGF1也比正常细胞多。可能对IGF1作用起反调节作用的IGFBP3在BDL胆管细胞中减少。IGF1通过p-IGF1R、IRS1、IRS-2、p-ERK1/2和p-AKT的过表达促进胆管细胞增殖。GH诱导分离的胆管细胞中IGF1的表达和释放，并重现了IGF1的作用，但IGF1-R阻断抗体可消除GH的作用，提示IGF1是GH的介质。最后，IGF1和17β-雌二醇相互增强对胆管细胞的增殖作用，且在受体和受体后水平均有相互作用。
胆管细胞对GH作出反应，产生并释放IGF1，IGF1通过涉及IGF1-R、IRS1/2以及ERK和PI3激酶途径的转导途径调节细胞增殖。胆管上皮是GH/IGF1肝脏轴的靶标。
