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Departments of
*
Pathology and
Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; and
Department of Hematology, Erasmus University, Rotterdam, The Netherlands
P-glycoprotein (Pgp) and vaults are associated with multidrug
resistance in tumor cells, but their physiological functions are not
yet clear. Pgp, the prototypical transmembrane transporter molecule,
may also facilitate the migration of skin dendritic cells (DC).
Vaultsribonucleoprotein cell organelles, frequently overexpressed in
Pgp-negative drug-resistant tumor cellshave also been associated with
intracellular transport processes. Given the pivotal role of DC in
dealing with exposure to potentially harmful substances, the present
study was set out to examine the expression of Pgp and vaults during
differentiation and maturation of DC. DC were obtained from different
sources, including blood-derived monocytes, CD34+
mononuclear cells, and chronic myeloid leukemia cells. Whereas flow
cytometric and immunocytochemical analyses showed slightly augmented
levels of Pgp, up-regulation of vault expression during DC culturing
was strong, readily confirmed by Western blotting, and independent of
the source of DC. In further exploring the functional significance of
vault expression, it was found that supplementing DC cultures with
polyclonal or mAbs against the major vault protein led to lower
viabilities of LPS- or TNF-
-matured monocytes-DC. Moreover,
expression of critical differentiation, maturation, and costimulatory
molecules, including CD1a and CD83, was reduced and their capacity to
induce Ag-specific T cell proliferative and IFN-
release responses
was impaired. These data point to a role for vaults in both DC survival
and functioning as APC.
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