Iron is a regulatory component of human IL-1 beta production support for regional variability in the lung

The human lung accumulates iron with senescence. Smoking escalates the accu mulation of iron, and we have demonstrated regional variability in the accu mulation of iron in smokers' lungs. Iron has been reported to influence the production of a number of proinflammatory mediators, including human inter leukin (IL)-1 beta. We postulated that we could (1) demonstrate regional di fferences in the release of IL-1 beta from human alveolar macrophages and ( 2) influence the production of IL-1 beta in human macrophages by altering i ntracellular iron concentrations. To test these hypotheses, alveolar macrop hages were obtained by independent lavage of the upper and lower lobes of h ealthy volunteers (both smokers and nonsmokers), after which the ability of each population to secrete IL-1 beta was quantified, together with their a bility to produce tumor necrosis factor-alpha, IL-6, and IL-8. Additionally , we established an in vitro model of "iron-loaded" cells of the human myel omonocytic cell line THP-1 in order to examine more directly the effect of iron and its chelation on the secretion of IL-1 beta. We report here that a n intracellular, chelatable pool of iron expands with exogenous iron-loadin g as well as with lipopolysaccharide (LPS) stimulation and appears to suppr ess transcription of IL-1 beta, whereas shrinkage of this pool by early che lation augments transcription of IL-1 beta beyond that induced by LPS alone . And finally, we demonstrate a regional relationship in the lung between e xcess alveolar iron and the production of human alveolar macrophage-derived IL-1 beta, suggesting a partnership between iron and inflammation that may have clinical significance, especially in relation to lung diseases with a regional predominance.