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- Title
Glucocorticoid-induced leucine zipper is downregulated in human alveolar macrophages upon Toll-like receptor activation.
- Authors
Hoppstädter, Jessica; Diesel, Britta; Eifler, Lisa K.; Schmid, Tobias; Brüne, Bernhard; Kiemer, Prof. Alexandra K.
- Abstract
Induction of the glucocorticoid-induced leucine zipper ( GILZ) by glucocorticoids plays a role in their antiinflammatory action, whereas GILZ expression is reduced under inflammatory conditions. The mechanisms regulating GILZ expression during inflammation, however, have not yet been characterized. Here, we investigated GILZ expression in human alveolar macrophages ( AMs) following Toll-like receptor (TLR) activation. Macrophages were shown to predominantly express GILZ transcript variant 2. Lipopolysaccharide-treated AMs, THP-1 cells, and lungs of lipopolysaccharide-exposed mice displayed decreased GILZ protein and m RNA levels. The effect was strictly dependent on the adapter molecule My D88, as shown by using specific ligands or a knockdown strategy. Investigations on the functional significance of GILZ downregulation performed by GILZ knockdown revealed a proinflammatory response, as indicated by increased cytokine expression and NF-κ B activity. We found that TLR activation reduced GILZ m RNA stability, which was mediated via the GILZ 3′-untranslated region. Finally, involvement of the m RNA-binding protein tristetraprolin ( TTP) is suggested, since TTP overexpression or knockdown modulated GILZ expression and TTP was induced in a My D88-dependent fashion. Taken together, our data show a My D88- and TTP-dependent GILZ downreg-ulation in human macrophages upon TLR activation. Suppression of GILZ is mediated by m RNA destabilization, which might represent a regulatory mechanism in macrophage activation.
- Publication
European Journal of Immunology, 2012, Vol 42, Issue 5, p1282
- ISSN
0014-2980
- Publication type
Article
- DOI
10.1002/eji.201142081