Abstract
GILZ (glucocorticoid-induced leucine zipper) is inducible by glucocorticoids and plays a key role in their mode of action. GILZ attenuates inflammation mainly by inhibition of NF-κB and mitogen-activated protein 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. The up-regulation of GILZ was neither associated with glucocorticoid receptor activation nor with transcriptional induction or mRNA or protein stabilization but was a result of enhanced translation. Because the GILZ 3'-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 its anti-inflammatory action by induction of GILZ in macrophages. Experiments with LPS-activated bone marrow-derived macrophages from wild-type and GILZ knock-out 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.
Highlights
The polyphenol curcumin is the principal bioactive compound of turmeric (Curcuma longa) preparations, which are commonly used as traditional remedies or spices
In the first series of experiments we examined whether curcumin influences the expression of glucocorticoid-induced leucine zipper (GILZ) in the macrophagelike cell lines RAW264.7 and U937
glucocorticoid receptor (GR) translocation was absent in curcumin-treated cells (Fig. 2A and supplemental Fig. 1), indicating that the up-regulation of GILZ by curcumin was not associated with GR activation
Summary
The polyphenol curcumin (diferuloylmethane) is the principal bioactive compound of turmeric (Curcuma longa) preparations, which are commonly used as traditional remedies or spices. Curcumin administration reduced the infiltration of macrophages into the glomeruli and impaired the expression of proinflammatory cytokines, such as tumor necrosis factor-␣ (TNF-␣) [8]. The anti-inflammatory effects of curcumin in macrophages and other mononuclear cells are associated with its ability to suppress nuclear factor B (NF-B) signaling (8 –13). GILZ-dependent Anti-inflammatory Effects of Curcumin tory transcription factors NF-B and activator protein AP-1, thereby inhibiting their translocation (14 –17). Due to its strong induction by glucocorticoids (GCs) in the thymus, early studies on GILZ concentrated on its effects on thymocytes and T-lymphocytes [21]. Several reports indicated that the effects of GILZ overexpression are similar to GC treatment regarding the induction of thymocyte and T-lymphocyte apoptosis [14, 17, 21,22,23]. Lack of GILZ impairs GCinduced apoptosis in B-lymphocytes [24]
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