Inhibition of secretory Phospholipase A2 Group IIa by thyroid hormone

Abstract

Secretory phospholipase A2 group IIa (PLA2g2a) is involved in multiple biological processes including inflammation and atherosclerosis. In this study, we investigated the regulation of PLA2g2a by thyroid hormone (T3). T3 stimulates expression of genes through the binding of the nuclear T3 receptor (TR) to T3 response elements (TRE). The liganded TRβ recruits transcriptional coactivators to stimulate gene expression. However, as many genes are down regulated by T3 as are stimulated. We found that T3 suppressed the expression of the PLA2g2a gene in hepatocytes, human HepG2 cells and in vivo in rats. To gain insight into the mechanism of transcriptional repression, we cloned the PLA2g2a promoter. We identified a negative TRE (nTRE) in the promoter that bound the T3 receptor as a heterodimer with the retinoid X receptor (RXR). Mutation of the nTRE eliminated the ability of T3 to inhibit PLA2g2a. Knockdown of the nuclear corepressors (NCoR) blocked the T3 inhibition of PLA2g2a. In conclusion our experiments demonstrate a novel inverse recruitment mechanism where liganded TRβ recruits corepressors to inhibit PLA2g2a expression. These results suggest that in addition to the well known role of T3 in regulating genes involved in hepatic metabolism T3 may also modulate the expression of inflammatory genes.This work was supported by National Institute of Health.