De Silva Matharage S I, Dayton Adam W, Rhoten Lance R, Mallett John W, Reese Jared C, Squires Mathieu D, Dalley Andrew P, Porter James P, Judd Allan M
Department of Physiology and Developmental Biology and Neuroscience Center, Brigham Young University, 4005 LSB, Provo, Utah 84602, United States.
Department of Physiology and Developmental Biology and Neuroscience Center, Brigham Young University, 4005 LSB, Provo, Utah 84602, United States.
Steroids. 2018 Jun;134:53-66. doi: 10.1016/j.steroids.2018.02.009. Epub 2018 Mar 1.
In bovine adrenal zona fasciculata (ZF) and NCI-H295R cells, interleukin-6 (IL-6) increases cortisol release, increases expression of steroidogenic acute regulatory protein (StAR), cholesterol side chain cleavage enzyme (P450scc), and steroidogenic factor 1 (SF-1) (increases steroidogenic proteins), and decreases the expression of adrenal hypoplasia congenita-like protein (DAX-1) (inhibits steroidogenic proteins). In contrast, IL-6 decreases bovine adrenal zona reticularis (ZR) androgen release, StAR, P450scc, and SF-1 expression, and increases DAX-1 expression. Adenosine monophosphate (AMP) activated kinase (AMPK) regulates steroidogenesis, but its role in IL-6 regulation of adrenal steroidogenesis is unknown. In the present study, an AMPK activator (AICAR) increased (P < 0.01) NCI-H295R StAR promoter activity, StAR and P450scc expression, and the phosphorylation of AMPK (PAMPK) and acetyl-CoA carboxylase (PACC) (indexes of AMPK activity). In ZR (decreased StAR, P450scc, SF-1, increased DAX-1) (P < 0.01) and ZF tissues (increased StAR, P450scc, SF-1, decreased DAX-1) (P < 0.01), AICAR modified StAR, P450scc, SF-1 and DAX-1 mRNAs/proteins similar to the effects of IL-6. The activity (increased PAMPK and PACC) (P < 0.01) of AMPK in the ZF and ZR was increased by AICAR and IL-6. In support of an AMPK role in IL-6 ZF and ZR effects, the AMPK inhibitor compound C blocked (P < 0.01) the effects of IL-6 on the expression of StAR, P450scc, SF-1, and DAX-1. Therefore, IL-6 modification of the expression of StAR and P450scc in the ZF and ZR may involve activation of AMPK and these changes may be related to changes in the expression of SF-1 and DAX-1.
在牛肾上腺束状带（ZF）和NCI-H295R细胞中，白细胞介素-6（IL-6）可增加皮质醇释放，增加类固醇生成急性调节蛋白（StAR）、胆固醇侧链裂解酶（P450scc）和类固醇生成因子1（SF-1）的表达（增加类固醇生成蛋白），并降低先天性肾上腺发育不全样蛋白（DAX-1）的表达（抑制类固醇生成蛋白）。相比之下，IL-6可降低牛肾上腺网状带（ZR）雄激素释放、StAR、P450scc和SF-1表达，并增加DAX-1表达。单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）调节类固醇生成，但其在IL-6调节肾上腺类固醇生成中的作用尚不清楚。在本研究中，一种AMPK激活剂（AICAR）增加了（P < 0.01）NCI-H295R细胞中StAR启动子活性、StAR和P450scc表达，以及AMPK（PAMPK）和乙酰辅酶A羧化酶（PACC）的磷酸化（AMPK活性指标）。在ZR组织（StAR、P450scc、SF-1降低，DAX-1增加）（P < 0.01）和ZF组织（StAR、P450scc、SF-1增加，DAX-1降低）（P < 0.01）中，AICAR对StAR、P450scc、SF-1和DAX-1 mRNA/蛋白的修饰与IL-6的作用相似。AICAR和IL-6增加了ZF和ZR中AMPK的活性（PAMPK和PACC增加）（P < 0.01）。为支持AMPK在IL-6对ZF和ZR的作用中的作用，AMPK抑制剂化合物C阻断了（P < 0.01）IL-6对StAR、P450scc、SF-1和DAX-1表达的影响。因此，IL-6对ZF和ZR中StAR和P450scc表达的修饰可能涉及AMPK的激活，且这些变化可能与SF-1和DAX-1表达的变化有关。
