Lafdil Fouad, Chobert Marie Noële, Couchie Dominique, Brouillet Arthur, Zafrani Elie Serge, Mavier Philippe, Laperche Yannick
INSERM, U581, Créteil, France.
Hepatology. 2006 Jul;44(1):228-39. doi: 10.1002/hep.21237.
The protein product of the growth arrest-specific gene 6 (Gas6) is a secreted ligand for tyrosine kinase receptors, among which Axl is the most widely distributed and displays the highest affinity for Gas6. The Gas6/Axl signaling pathway has been increasingly implicated in growth and survival processes occurring during development and tissue repair. In liver, after an acute or chronic injury, repair involves macrophages and hepatic stellate cells (HSC) activated into myofibroblastic cells (HSC/MFB), which produce cytokines and matrix proteins. We investigated the expression and the role of Gas6 and its receptor Axl in liver repair. Three days after CCl4-induced liver injury in the rat, we detected the expression of Gas6 in ED1-positive macrophages as well as in desmin-positive HSC, which accumulated in injured areas. Axl, the high-affinity receptor for Gas6, was detected in macrophages, HSC, and HSC/MFB. In vitro, expression of gamma-carboxylated Gas6 was strongly induced in HSC along with their transformation into myofibroblasts, and it exerted an anti-apoptotic effect on both HSC and HSC/MFB mediated by the Axl/PI3-kinase/Akt pathway. In conclusion, Gas6 is a survival factor for these cells and we suggest that Gas6, secreted by macrophages and HSC/MFB in vivo after liver injury, promotes HSC and HSC/MFB survival and might support transient HSC/MFB accumulation during liver healing.
生长停滞特异性基因6（Gas6）的蛋白质产物是酪氨酸激酶受体的分泌型配体，其中Axl分布最为广泛，且对Gas6显示出最高亲和力。Gas6/Axl信号通路越来越多地涉及发育和组织修复过程中的生长与存活过程。在肝脏中，急性或慢性损伤后，修复过程涉及巨噬细胞和被激活为肌成纤维细胞（HSC/MFB）的肝星状细胞（HSC），这些细胞会产生细胞因子和基质蛋白。我们研究了Gas6及其受体Axl在肝脏修复中的表达及作用。在大鼠四氯化碳诱导的肝损伤后三天，我们检测到Gas6在ED1阳性巨噬细胞以及在损伤区域积聚的结蛋白阳性HSC中表达。Gas6的高亲和力受体Axl在巨噬细胞、HSC和HSC/MFB中被检测到。在体外，随着HSC向肌成纤维细胞的转化，γ-羧化Gas6的表达在HSC中被强烈诱导，并且它通过Axl/PI3激酶/Akt途径对HSC和HSC/MFB均发挥抗凋亡作用。总之，Gas6是这些细胞的存活因子，我们认为肝脏损伤后体内巨噬细胞和HSC/MFB分泌的Gas6可促进HSC和HSC/MFB的存活，并可能支持肝脏愈合过程中短暂的HSC/MFB积聚。
