Am. J. Respir. Cell Mol. Biol.,
Volume 23, Number 1, July, 2000 112-119
Iron Is a Regulatory Component of Human IL-1
Production
Support for Regional Variability in the Lung
Amy R.
O'Brien-Ladner,
Stan R.
Nelson,
William J.
Murphy,
Barbara M.
Blumer,
and
Lewis J.
Wesselius
Division of Pulmonary and Critical Care Medicine, Departments of Medicine, Anatomy and Cell Biology, and Pathology and Laboratory
Medicine, University of Kansas School of Medicine; Kansas City Veterans Administration; and the Wilkinson Laboratory of the Kansas
Cancer Institute, Kansas City, Kansas
The human lung accumulates iron with senescence. Smoking
escalates the accumulation of iron, and we have demonstrated regional variability in the accumulation of iron in
smokers' lungs. Iron has been reported to influence the production of a number of proinflammatory mediators, including
human interleukin (IL)-1
. We postulated that we could (1)
demonstrate regional differences in the release of IL-1 from
human alveolar macrophages and (2) influence the production of IL-1 in human macrophages by altering intracellular iron concentrations. To test these hypotheses, alveolar macrophages were obtained by independent lavage of the upper
and lower lobes of healthy volunteers (both smokers and nonsmokers), after which the ability of each population to secrete
IL-1 was quantified, together with their ability to produce tumor necrosis factor-
, IL-6, and IL-8. Additionally, we established an in vitro model of "iron-loaded" cells of the human
myelomonocytic cell line THP-1 in order to examine more directly the effect of iron and its chelation on the secretion of
IL-1. We report here that an intracellular, chelatable pool of
iron expands with exogenous iron-loading as well as with lipopolysaccharide (LPS) stimulation and appears to suppress
transcription of IL-1, whereas shrinkage of this pool by early
chelation augments transcription of IL-1 beyond that induced by LPS alone. And finally, we demonstrate a regional relationship in the lung between excess alveolar iron and the production of human alveolar macrophage-derived IL-1,
suggesting a partnership between iron and inflammation that
may have clinical significance, especially in relation to lung
diseases with a regional predominance.
