Induction of glucocorticoid-induced leucine zipper (GILZ) contributes to anti-inflammatory effects of the natural product curcumin in macrophages

GILZ is inducible by glucocorticoids and plays a key role in their mode of action. GILZ attenuates inflammation mainly by inhibition of NF-κB and MAP kinase activation but does not seem to be involved in the severe side effects observed after glucocorticoid treatment. Therefore, GILZ might be a promising target for new therapeutic approaches. The present work focuses on the natural product curcumin, which has previously been reported to inhibit NF-κB. GILZ was inducible by curcumin in macrophage cell lines, primary human monocyte-derived macrophages, and murine bone marrow-derived macrophages (BMMs). The upregulation of GILZ was neither associated with glucocorticoid receptor activation nor with transcriptional induction, mRNA or protein stabilization, but was a result of enhanced translation. Since the GILZ 3 prime-UTR contains AU-rich elements (AREs), we analyzed the role of the mRNA binding protein HuR, which has been shown to promote the translation of ARE-containing mRNAs. Our results suggest that curcumin treatment induces HuR expression. An RNA-immunoprecipitation assay confirmed that HuR can bind GILZ mRNA. In accordance, HuR overexpression led to increased GILZ protein levels but had no effect on GILZ mRNA expression. Our data employing siRNA in LPS-activated RAW264.7 macrophages show that curcumin facilitates this anti-inflammatory action by induction of GILZ in macrophages. Experiments with LPS-activated BMMs from wild-type and GILZ knockout mice demonstrated that curcumin inhibits the activity of inflammatory regulators, such as NF-κB or ERK and subsequent TNF-α production via GILZ. In summary, our data indicate that HuR-dependent GILZ induction contributes to the anti-inflammatory properties of curcumin.