TNF gene expression in macrophage activation and endotoxin tolerance

Abstract

TNF is an inflammatory cytokine that plays a critical role in the acute phase response to infection, and its dysregulation has been implicated in the pathology of several inflammatory and autoimmune disorders. TNF gene expression is regulated in a cell type- and inducer-specific manner that involves chromatin alterations at both the TNF promoter and distal DNase I hypersensitive (DH) sites within the TNF/LT locus. While the mechanisms underlying TNF gene activation in monocytes/macrophages and T cells have been studied intensively, the mechanisms of enhanced, repressed, and restored TNF gene expression in the context of classical macrophage activation and endotoxin tolerance remain largely unknown. We set out to understand how TNF gene expression is modulated during these biological processes by characterizing the chromatin environment of the TNF/LT locus.