Differential regulation of human alveolar macrophage-derived interleukin-1beta and tumor necrosis factor-alpha 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-alpha (TNF-alpha) and interleukin-1-beta (IL-1-beta) 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-beta, but not TNF-alpha, from AMs from smokers and nonsmokers. The DFA augmentation of LPS-induced IL-1-beta was more pronounced in smokers' AMs than in those from non-smokers (4.5-fold vs 2.6-fold increase). The addition of FeCl3 to DFA diminished the augmenting effect on the release of IL-1-beta, suggesting that the mechanism of action involved iron chelation. Conversely, as the intensity of iron chelation increased, the release of IL-1-beta and TNF-alpha 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.
O'Brien-Ladner
A R
AR
Department of of Medicine, University of Kansas School of Medicine, USA.
Blumer
B M
BM
Wesselius
L J
LJ
D000328:Adult; D015152:Blotting, Northern; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D002614:Chelating Agents / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000032:analysis / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D012907:Smoking / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D002614:Chelating Agents; D016166:Free Radical Scavengers; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C038983:1,3-dimethylthiourea; D007501:Iron; D013890:Thiourea; D003676:Deferoxamine