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Department of Biology, Virginia Commonwealth University, Richmond, VA 23284
The c-kit protooncogene encodes a receptor tyrosine
kinase that is known to play a critical role in hemopoiesis and is
essential for mast cell growth, differentiation, and cytokine
production. Studies have shown that the Th2 cytokine IL-4 can
down-regulate Kit expression on human and murine mast cells, but the
mechanism of this down-regulation has remained unresolved. Using mouse
bone marrow-derived mast cells, we demonstrate that IL-4-mediated Kit
down-regulation requires STAT6 expression and
phosphotidylinositide-3'-kinase activation. We also find that the Th2
cytokine IL-10 potently down-regulates Kit expression. IL-4 enhances
IL-10-mediated inhibition in a manner that is STAT6 independent and
phosphotidylinositide-3'-kinase dependent. Both IL-4- and
IL-10-mediated Kit down-regulation were coupled with little or no
change in c-kit mRNA levels, no significant change in
Kit protein stability, but decreased total Kit protein expression.
Inhibition of Kit expression by IL-4 and IL-10 resulted in a loss of
Kit-mediated signaling, as evidenced by reduced IL-13 and TNF-
mRNA
induction after stem cell factor stimulation. These data offer a role
for STAT6 and phosphotidylinositide-3'-kinase in IL-4-mediated Kit
down-regulation, coupled with the novel observation that IL-10 is a
potent inhibitor of Kit expression and function. Regulating Kit
expression and signaling may be essential to controlling mast
cell-mediated inflammatory responses.
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