The androgen metabolite, 5?-androstane-3?,17?-diol, decreases cytokine-induced cyclooxygenase-2, vascular cell adhesion molecule-1 expression, and P-glycoprotein expression in male human brain microvascular endothelial cells.

ABSTRACT: P-glycoprotein (Pgp), a multiple drug resistance transporter expressed by vascular endothelial cells, is a key component of the blood-brain barrier and has been shown to increase after inflammation. The nonaromatizable androgen, dihydrotestosterone (DHT), decreases inflammatory markers in vascular smooth muscle cells, independent of androgen receptor (AR) stimulation. The principal metabolite of DHT, 5?-androstane-3?,17?-diol (3?-diol), activates estrogen receptor (ER)? and similarly decreases inflammatory markers in vascular cells. Therefore, we tested the hypothesis that either DHT or 3?-diol decrease cytokine-induced proinflammatory mediators, vascular cell adhesion molecule-1 (VCAM-1) and cyclooxygenase-2 (COX-2), to regulate Pgp expression in male primary human brain microvascular endothelial cells (HBMECs). Using RT-qPCR, the mRNAs for AR, ER?, and ER? and steroid metabolizing enzymes necessary for DHT conversion to 3?-diol were detected in male HBMECs demonstrating that the enzymes and receptors for production of and responsiveness to 3?-diol are present. Western analysis showed that 3?-diol reduced COX-2 and Pgp expression; the effect on Pgp was inhibited by the ER antagonist, ICI-182,780. IL-1?-caused an increase in COX-2 and VCAM-1 that was reduced by either DHT or 3?-diol. 3?-diol also decreased cytokine-induced Pgp expression. ICI-182,780 blocked the effect of 3?-diol on COX-2 and VCAM-1, but not Pgp expression. Therefore, in cytokine-stimulated male HBMECs, the effect of 3?-diol on proinflammatory mediator expression is ER dependent, whereas its effect on Pgp expression is ER independent. These studies suggest a novel role of 3?-diol in regulating blood-brain barrier function and support the concept that 3?-diol can be protective against proinflammatory mediator stimulation.

SUBMITTER: Zuloaga KL 

PROVIDER: S-EPMC3512076 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature