Molecular regulation of iron homeostasis and resistance to infection in alcoholics

Abstract

Chronic alcohol abuse is associated with both an altered response to infection and deranged iron homeostasis. While both clinical manifestations are well known, the inter-relationships between alcohol and iron and the response to infection are not. The recent identification of a plethora of iron regulatory and transport proteins has now begun to explain these relationships. This article outlines the current state of knowledge on cellular iron homeostasis, with particular reference to the iron regulatory proteins (IRP1, IRP2 and HFE) and the iron membrane transport proteins, two of which have been shown to be members of the natural resistance- associated macrophage protein family (Nramp1 and 2). Following this introduction, the response of the body to infection, in terms of iron withholding is discussed at the cellular level, especially in terms of the macrophage and its cytokine-mediated responses. Prior alterations to body iron status are also considered in this section. The effect of alcohol alone on the body's response to infection is then outlined, principally in terms of the macrophage function and cytokine regulation. These are then combined to correlate the clinical and experimental observations with known derangements produced by the individual insults of alcohol and altered iron homeostasis. on the response to infection. Particular attention is paid not only to cytokine/chemokine actions, but also to the consequences of the altered production of reactive oxygen and nitrogen species. Finally, the possible mechanisms by which alcohol and altered iron homeostasis lead to tissue damage during infection.