Iron regulation of hepatic macrophage TNFα expression 1,2

Abstract

Sustained TNFα induction is central to the pathogenesis of chronic liver disease including alcoholic liver disease (ALD). However, molecular understanding of this abnormality at the cellular level remains elusive. Redox regulation of NF-κB is critical in the transcriptional control of TNFα expression. Evidence supports that increased iron storage in hepatic macrophages (HM) is causally associated with accentuated and sustained NF-κB activation in these cells in ALD. Treatment of cultured HM with a lipophilic iron chelator (deferiprone) abrogates LPS-induced NF-κB activation. HM from an animal model of ALD have increased nonheme iron content accompanied by increased generation of EPR-detected radicals, NF-κB activation, and TNFα induction, all of which are normalized by ex vivo treatment of the cells with deferiprone. A moderate increase in the nonheme iron content in HM by erythrophagocytosis, promotes subsequent LPS-stimulated NF-κB activation in a hemeoxygenase-dependent manner. Recent evidence also suggests a role of intracellular low molecular weight iron in the early signal transduction for LPS-mediated NF-κB activation.