Abstract
Cyclooxygenase‐2 (COX‐2) plays an important role in rheumatoid arthritis and therefore, has been a major target for anti‐arthritis therapies. The expression of COX‐2 is induced by inflammatory cytokines such as TNF‐α and IL‐1β, and inhibited by glucocorticoids. However, the molecular mechanisms underlying the anti‐inflammatory and immune suppressive actions of glucocorticoids are not well defined. Here we report that glucocorticoid‐induced leucine zipper (GILZ) mimics glucocorticoid action and inhibits inflammatory cytokine‐induced COX‐2 expression in bone marrow mesenchymal stem cells, the cells that have been recently implicated in the pathogenesis and progression of rheumatoid arthritis. Using a retrovirus‐mediated gene expression approach we demonstrate that overexpression of GILZ inhibits TNF‐α and IL‐1β‐induced COX‐2 mRNA and protein expression, and knockdown of GILZ by shRNA reduces glucocorticoid inhibition of cytokine‐induced COX‐2 expression. Consistent to these results, overexpression of GILZ also inhibits NF‐κB‐mediated COX‐2 promoter activity. Finally, we show that GILZ inhibits COX‐2 expression by blocking NF‐κB nuclear translocation. Our results suggest that GILZ is a key glucocorticoid effect mediator and that GILZ may have therapeutic value for novel anti‐inflammation therapies. J. Cell. Biochem. 103: 1760–1771, 2008. © 2007 Wiley‐Liss, Inc.