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Departments of Microbiology and Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio
Correspondence: Bruce S. Zwilling, Department of Microbiology, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210. E-mail: zwilling.1{at}osu.edu
Nramp1 is an important determinant of innate resistance of
macrophages to the growth of intracellular microorganisms. We
previously showed that Nramp1 functions to transport iron from the
cytoplasm into phagosomes of Mycobacterium avium-infected
macrophages. The purpose of this investigation was to further
characterize the factors that regulate Nramp1-mediated iron transport
into phagosomes. Treatment of Nramp1Gly169
macrophages with the lysomotrophic agents chloroquine or ammonium
chloride reduced the import of iron significantly. We found that
macrophage-activating cytokines, including TNF-
,
IFN-
, IL-1, and GM-CSF, when added prior to M.
avium, increased the transport of iron into the phagosome. This
increase in iron transport was not a result of an increased amount of
Nramp1 protein in the phagosome nor to new protein synthesis. Treatment
of Nramp1Gly169-transfected macrophages with
inhibitors of protein kinase C (PKC) diminished the import of iron into
the phagosomes. Iron import was inhibited by an anti-Nramp1 antibody
against the putative fourth outer-loop region of Nramp1 but not by an
anti-Nramp1 antibody against the carboxy terminus. The significance of
these results on the orientation of Nramp1 in the phagosome membrane
and on the transport of iron is discussed.
Key Words: Fe-citrate • PKC • Nramp1Asp169 • cytokines
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