Glycoprotein130 (gp130) is an important signal transducer in the interleukin-6 (IL-6) trans-signaling pathway, which plays a crucial role in chronic inflammation in atherosclerosis. Studies suggest that estrogen can inhibit IL-6/gp130 signaling and reduce the risk of coronary artery disease, but the precise mechanism is unclear. The aim of this study was to investigate whether and how estrogen regulates gp130 in human umbilical vein endothelial cells (HUVECs). HUVECs were first treated with IL-6 and soluble IL-6 receptor (sIL-6R) to induce inflammation, then treated with estradiol. We then measured the expression of gp130, a disintegrin and metalloproteinase 10 (ADAM10) and 17 (ADAM17) by RT-PCR and western blot. Levels of soluble gp130 (sgp130) in the culture supernatant were measured by ELISA. We found that IL-6 and sIL-6R increased expression of gp130 protein and decreased levels of sgp130 protein, without affecting gp130 mRNA levels. Estradiol treatment reversed these effects in a concentration- and time-dependent manner. These effects were regulated by ADAM10 and ADAM17 via an estrogen receptor alpha/beta-dependent mechanism. These results shed further light on the mechanism underlying the clinical effects of estrogen therapy in atherosclerosis and coronary artery disease. (C) 2020 Elsevier Inc. All rights reserved.