Regulation of expression of the rat serine protease inhibitor 2.3 gene by glucocorticoids and interleukin-6. A complex and unusual interplay between positive and negative cis-acting elements
Abstract
The rat serine protease inhibitor 2.3 gene (spi 2.3) is almost completely silent in normal animals and is transiently expressed during acute inflammation. It encodes a potential anti-elastase which is likely to play a major physiological role for the host defense. Two well-known inflammatory mediators, glucocorticoids and interleukin-6 (IL-6) activate the spi 2.3 promoter and increase steady-state levels of mRNA in cultured hepatocytes. GC activation is mediated by a single glucocorticoid-response element which seems to act autonomously. A unique array of four functional IL-6-response sites was identified in the spi 2.3 promoter. Three of them (C-II--IV) bear structural identity to the CCAAT/enhancer-binding-protein-binding site consensus sequence, whereas the fourth closely resembles the consensus kappa B nuclear factor recognition motif. The C-IV element, which is the most active, contains the motif 5'-CTGGGA and binds the IL-6-inducible acute-phase response factor present in liver nuclear extracts from inflamed rats. Both basal and IL-6-dependent activities of each individual cytokine-response element tested separately are strongly down regulated by a recently identified regulatory sequence, located in the 3' untranslated re...Continue Reading
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