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German Diabetes Research Institute at the Heinrich-Heine-University of Düsseldorf, Düsseldorf, Germany
Previous studies have shown that human heat shock protein (hsp) 60
elicits a strong proinflammatory response in cells of the innate immune
system with CD14, Toll-like receptor (TLR) 2, and TLR4 as mediators of
signaling, but probably not of binding. In the present study, we
directly demonstrate binding of hsp60 to the macrophage surface and
find the binding receptor for hsp60 different from the previously
described common receptor for several other heat shock proteins,
including hsp70, hsp90, and gp96. Fluorescence-labeled human hsp60
bound to cell surfaces of the murine macrophage lines J774 A.1 and
RAW264.7 and to mouse bone marrow-derived macrophages. By flow
cytometry, we could demonstrate for the first time that hsp60 binding
to macrophages occurred at submicromolar concentrations, is saturable,
and can be competed by unlabeled hsp60, but not by unrelated proteins,
thus confirming the classic characteristics of specific ligand-receptor
interactions. Binding of hsp60 at 4°C was followed by endocytosis at
37°C. Hsp60 binding to macrophages could not be competed by excess
hsp70, hsp90, or gp96, all of which share the
2-macroglobulin receptor as binding site. Hsp60 binding
occurred in the absence of surface TLR4. However, no cytokine response
was induced by hsp60 in TLR4-deficient macrophages. We conclude that
hsp60 binds to a stereo-specific receptor on macrophages, and that
different surface molecules are engaged in binding and signal
transduction. Furthermore, the binding site for hsp60 is separate from
the common receptor for hsp70, hsp90, and gp96, which suggests an
independent role of hsp60 as danger Ag and in
immunoregulation.
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