Spector M S, Auer K L, Jarvis W D, Ishac E J, Gao B, Kunos G, Dent P
Department of Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0058, USA.
Mol Cell Biol. 1997 Jul;17(7):3556-65. doi: 10.1128/MCB.17.7.3556.
To study the mechanisms by which catecholamines regulate hepatocyte proliferation after partial hepatectomy (PHX), hepatocytes were isolated from adult male rats 24 h after sham operation or two-thirds PHX and treated with catecholamines and other agonists. In freshly isolated sham cells, p42 mitogen-activated protein (MAP) kinase activity was stimulated by the alpha1-adrenergic agonist phenylephrine (PHE). Activation of p42 MAP kinase by growth factors was blunted by pretreatment of sham hepatocytes with glucagon but not by that with the beta2-adrenergic agonist isoproterenol (ISO). In PHX cells, the ability of PHE to activate p42 MAP kinase was dramatically reduced, whereas ISO became competent to inhibit p42 MAP kinase activation. PHE treatment of sham but not PHX and ISO treatment of PHX but not sham hepatocytes also activated the stress-activated protein (SAP) kinases p46/54 SAP kinase and p38 SAP kinase. These data demonstrate that an alpha1- to beta2-adrenergic receptor switch occurs upon PHX and results in an increase in SAP kinase versus MAP kinase signaling by catecholamines. In primary cultures of hepatocytes, ISO treatment of PHX but not sham cells inhibited [3H]thymidine incorporation. In contrast, PHE treatment of sham but not PHX cells stimulated [3H]thymidine incorporation, which was reduced by approximately 25 and approximately 95% with specific inhibitors of p42 MAP kinase and p38 SAP kinase function, respectively. Inhibition of the p38 SAP kinase also dramatically reduced basal [3H]thymidine incorporation. These data suggest that p38 SAP kinase plays a permissive role in liver regeneration. Alterations in the abilities of catecholamines to modulate the activities of protein kinase A and the MAP and SAP kinase pathways may represent one physiological mechanism by which these agonists can regulate hepatocyte proliferation after PHX.
为研究儿茶酚胺在部分肝切除（PHX）后调节肝细胞增殖的机制，在假手术或三分之二肝切除术后24小时，从成年雄性大鼠分离肝细胞，并用儿茶酚胺和其他激动剂处理。在刚分离的假手术细胞中，α1 - 肾上腺素能激动剂去氧肾上腺素（PHE）刺激p42丝裂原活化蛋白（MAP）激酶活性。用胰高血糖素预处理假手术肝细胞可减弱生长因子对p42 MAP激酶的激活作用，但用β2 - 肾上腺素能激动剂异丙肾上腺素（ISO）预处理则无此作用。在PHX细胞中，PHE激活p42 MAP激酶的能力显著降低，而ISO则能够抑制p42 MAP激酶的激活。PHE处理假手术而非PHX肝细胞以及ISO处理PHX而非假手术肝细胞也激活了应激激活蛋白（SAP）激酶p46/54 SAP激酶和p38 SAP激酶。这些数据表明，PHX后发生了从α1 - 到β2 - 肾上腺素能受体的转换，导致儿茶酚胺介导的SAP激酶信号相对于MAP激酶信号增加。在肝细胞原代培养中，ISO处理PHX而非假手术细胞可抑制[3H]胸腺嘧啶核苷掺入。相反，PHE处理假手术而非PHX细胞可刺激[3H]胸腺嘧啶核苷掺入，分别用p42 MAP激酶和p38 SAP激酶功能的特异性抑制剂处理后，掺入量分别降低约25%和约95%。抑制p38 SAP激酶也显著降低基础[3H]胸腺嘧啶核苷掺入量。这些数据表明p38 SAP激酶在肝脏再生中起允许作用。儿茶酚胺调节蛋白激酶A以及MAP和SAP激酶途径活性的能力改变可能代表这些激动剂在PHX后调节肝细胞增殖的一种生理机制。
