Differential regulation of human alveolar macrophage-derived interleukin-1β and tumor necrosis factor-α by iron

Human lungs accumulate iron with the aging process. In some circumstances associated with lung injury (eg, smoking), this acquisition of iron in lung tissue and alveolar macrophages (AMs) is escalated. We hypothesized that excess cellular iron interfered with the production of tumor necrosis factor-α (TNF-α) and interleukin-1-(IL-1-β) by AMs. To examine this hypothesis, we acquired AMs from smokers and nonsmokers by bronchoalveolar lavage. AMs were stimulated by lipopolysaccharide (LPS), with and without deferoxamine (DFA), a chelator of iron. Enzyme-linked immunosorbent assay and Northern analysis were used to quantitate cytokine concentrations and mRNA. The addition of DFA increased the release of IL-1-β, but not TNF-α, from AMs from smokers and nonsmokers. The DFA augmentation of LPS-induced IL-I-β was more pronounced in smokers' AMs than in those from nonsmokers (4.5-fold vs 2.6-fold increase). The addition of FeCl₃ to DFA diminished the augmenting effect on the release of IL-1-β, suggesting that the mechanism of action involved iron chelation. Conversely, as the intensity of iron chelation increased, the release of IL-1-β and TNF-α decreased, as was also shown with hydroxyl radical scavenging by dimethylthiourea. This inhibition, however, occurred at very different thresholds for each cytokine. These data support a relationship between excess alveolar iron and the generation of inflammation within the lung.