Modulators of XXXX use nuclear factor-kappa B and @entity1178 sites to induce the @entity9302 and @entity10807 inhibitor, proteinase inhibitor 9.

@entity172 @entity9135 @entity32 @entity17590 @entity2451 @entity1356 @entity10807 @entity23601 @entity1178 @entity1639 @entity864 @entity9302
@entity17590 ) inhibits @entity9302 (interleukin (IL)-1beta-converting enzyme) and @entity10807 , thereby regulating production of the pro-inflammatory cytokine @entity1356 and susceptibility to @entity10807 -induced apoptosis. We show that cellular @entity17590 mRNA and protein are induced by @entity1356 , lipopolysaccharide, and @entity864 . We identified functional imperfect nuclear factor-kappaB (NF-kappaB) sites at -135 and -88 and a consensus @entity1178 ( @entity1178 ) site at -308 in the @entity17590 promoter region. Using transient transfections in HepG2 cells to assay @entity17590 promoter mutations, we find that mutational ablation of the @entity1178 site or of either NF-kappaB site reduces @entity1356 -induced expression of @entity17590 by approximately 60%. Mutational ablation of the two NF-kappaB sites and of the @entity1178 site nearly abolishes both basal and @entity1356 -induced expression of @entity17590 . Nuclear extracts from @entity1356 -treated HepG2 cells exhibited strong, @entity1356 -inducible binding to the NF-kappaB sites and to the @entity1178 site. Electrophoretic mobility shift assays show that after @entity1356 treatment @entity1178 / @entity1639 and @entity23601 bind to the @entity1178 site, whereas the @entity2451 / @entity9135 heterodimer binds to the two NF-kappaB sites. @entity172 induce @entity17590 , but induction of @entity17590 by @entity172 and @entity1356 is not synergistic. In transiently transfected, @entity172 receptor-positive HepG2ER7 cells, @entity172 do not interfere with @entity1356 induction, whereas @entity1356 exhibits dose-dependent repression of @entity172 -inducible @entity17590 expression. Our surprising finding that the pro-inflammatory cytokine @entity1356 strongly induces @entity17590 suggests a novel mechanism for regulating @entity32 and apoptosis through a negative feedback loop controlling expression of the anti-inflammatory and anti-apoptotic protein, @entity17590 .
