Melatonin suppresses cyclosporine A-induced autophagy in rat pituitary GH3 cells

作者：Yoo Yeong Min; Jeung Eui Bae^*

来源：Journal of Pineal Research, 2010, 48(3): 204-211.

DOI：10.1111/j.1600-079X.2010.00744.x

• autophagy
• cyclosporin A
• GH3 cells
• melatonin

Cyclosporine A (CsA) is a powerful immunosuppressive drug with side effects including the induction of chronic nephrotoxicity including endoplasmic reticulum (ER) stress in tubular cells. Recently, it was reported that autophagy is induced by ER stress and serves to alleviate the associated deleterious effects. In the current study, CsA treatment (0-100 mu m) decreased cell survival of rat pituitary GH3 cells in a dose-dependent manner. At concentrations ranging from 1.0 to 10 mu m, CsA induced a dose-dependent increase in the expression of microtubule-associated protein 1 light chain 3 (LC3)-I and LC3-II. Cells treated with 2.5 mu m CsA exhibited cytoplasmic vacuolation, indicating that CsA induces autophagy in rat pituitary GH3 cells. In the presence of 1.0-10 mu m CsA, the expression of catalase decreased while that of the ER stress markers, ER luminal binding protein (BiP) and inositol-requiring enzyme 1 alpha (IRE1 alpha), increased as compared those levels in untreated cells. These results suggested that CsA-induced autophagy is dependent on ER stress. To determine whether melatonin would protect cells against CsA-induced autophagy, we treated rat pituitary GH3 cells with melatonin in the presence of CsA. Melatonin treatment (100 and 200 mu m) suppressed autophagy induced by 2.5 and 5 mu m CsA. Furthermore, co-treatment with 100 mu m melatonin inhibited LC3-II expression, and increased catalase and phosphorylated p-ERK levels in the presence of 2.5 and 5 mu m CsA. BiP and IRE1 alpha expression in melatonin-co-treated cells was superior to that in cells treated with 2.5 and 5 mu m CsA alone. Thus, melatonin suppresses CsA-mediated autophagy in rat pituitary GH3 cells.

• 出版日期2010-4