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* Department of Immunology and Bacteriology, Western Infirmary, and
Center for Rheumatic Diseases, Royal Infirmary, Glasgow, United Kingdom;
Pharming Technologies, Leiden, The Netherlands; and
Instituto Finlay, Havana, Cuba
Lactoferrin (Lf) is an iron-binding protein of external secretions
and neutrophil secondary granules with antimicrobial and
immunomodulatory activities. To further define these properties of Lf,
we have investigated the response to Staphylococcus
aureus infection in transgenic mice carrying a functional human
Lf gene. The transgenic mice cleared bacteria
significantly better than congenic littermates, associated with a trend
to reduced incidence of arthritis, septicemia, and mortality. We
identified two pathways by which S. aureus clearance was
enhanced. First, human Lf directly inhibited the growth of S.
aureus LS-1 in vitro. Second, S. aureus-infected
transgenic mice exhibited enhanced Th1 immune polarization. Thus,
spleen cells from infected transgenic mice produced higher levels of
TNF-
and IFN-
and less IL-5 and IL-10 upon stimulation ex vivo
with the exotoxin toxic shock syndrome toxin-1 compared with
congenic controls. To confirm that these effects of Lf transgene
expression could occur in the absence of live bacterial infection, we
also showed that Lf-transgenic DBA/1 mice exhibited enhanced severity
of collagen-induced arthritis, an established model of Th1-induced
articular inflammation. Higher levels of stainable iron in the spleens
of transgenic mice correlated with human Lf distribution, but all other
parameters of iron metabolism did not differ between transgenic mice
and wild-type littermates. These results demonstrate that human Lf can
mediate both antimicrobial and immunomodulatory activities with
downstream effects on the outcome of immune pathology in infectious and
inflammatory disease.
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