Nuclear corepressors mediate the repression of phospholipase A2 group IIa gene transcription by thyroid hormone

Secretory phospholipase A2 group IIa (PLA2g2a) is associated with inflammation, hyperlipidemia, and atherogenesis. Transcription of the PLA2g2a gene is induced by multiple cytokines. Here, we report the surprising observation that thyroid hormone (T3) inhibited PLA2g2a gene expression in human and rat hepatocytes as well as in rat liver. Moreover, T3 reduced the cytokine-mediated induction of PLA2g2a, suggesting that the thyroid status may modulate aspects of the inflammatory response. In an effort to dissect the mechanism of repression by T3, we cloned the PLA2g2a gene and identified a negative T3 response element in the promoter. This T3 receptor (TRβ)-binding site differed considerably from consensus T3 stimulatory elements. Using in vitro and in vivo binding assays, we found that TRβ bound directly to the PLA2g2a promoter as a heterodimer with the retinoid X receptor. Knockdown of nuclear corepressor or silencing mediator for retinoid and thyroid receptors by siRNA blocked the T3 inhibition of PLA2g2a. Using chromatin immunoprecipitation assays, we showed that nuclear corepressor and silencing mediator for retinoid and thyroid receptors were associated with the PLA2g2a gene in the presence of T3. In contrast with the established role of T3 to promote coactivator association with TRβ, our experiments demonstrate a novel inverse recruitment mechanism in which liganded TRβ recruits corepressors to inhibit PLA2g2a expression.