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TNF, IFN-, and endotoxin increase expression of DMT1 in bronchial epithelial cells

¹Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill, North Carolina; ²Department of Biochemistry, State University of New York at Buffalo, Buffalo, New York; ³Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas; ⁴National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park, North Carolina; and ⁵Department of Internal Medicine, Duke University Medical Center, Durham, North Carolina

Submitted 4 December 2003 ; accepted in final form 2 March 2005

Regulation of the metal transport protein divalent metal transporter-1 (DMT1) may contribute to the uptake and detoxification of iron by cells resident in the respiratory tract. Inflammation has been associated with an increased availability of this metal resulting in an oxidative stress. Because proinflammatory cytokines and LPS have been demonstrated to affect an elevated expression of DMT1 in a macrophage cell line, we tested the hypothesis that tumor necrosis factor (TNF)-, interferon (IFN)-, and LPS increase DMT1 expression in airway epithelial cells. We used RT-PCR to detect mRNA for both –IRE DMT1 and +IRE DMT1 in BEAS-2B cells. Treatment with TNF-, IFN-, or LPS increased both forms. Western blot analysis also demonstrated an increase in the expression of both isoforms of DMT1 after these treatments. Twenty-four hours after exposure of an animal model to TNF-, IFN-, or LPS, a significant increase in pulmonary expression of –IRE DMT1 was seen by immunohistochemistry; the level of +IRE DMT1 was too low in the lung to be visualized using this methodology. Finally, iron transport into BEAS-2B cells was increased after inclusion of TNF-, IFN-, or LPS in the media. We conclude that proinflammatory cytokines and LPS increase mRNA and protein expression of DMT1 in airway cells in vitro and in vivo. Furthermore, both –IRE and +IRE isoforms are elevated after exposures. Increased expression of this protein appears to be included in a coordinated response of the cell and tissue where the function might be to diminish availability of metal.

membrane transporters; tumor necrosis factor; interferon; divalent metal transporter-1; lipopolysaccharide

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