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Interleukin-3 down-regulates its own receptor
SC Murthy, PH Sorensen, AL Mui and G Krystal
Terry Fox Laboratory, B.C. Cancer Research Centre, Vancouver.
To gain insight into the mechanisms involved in regulating murine
interleukin-3 (mIL-3) receptor expression, we have examined the effects of
mIL-3 and murine granulocyte-macrophage colony-stimulating factor (mGM-CSF)
on mIL-3 receptor internalization and re-expression and studied the
relationship between mIL-3 cell surface receptor density and growth factor
sensitivity. As a source of cells for our studies, we used a B6SUtA clone,
B6SUtA1, which grows equally well in mIL-3 or mGM- CSF when supplemented
with 20% fetal calf serum (FCS) in RPMI 1640. Intracellular processing
studies carried out in the presence and absence of methylamine suggested
that mIL-3 is cleaved at two specific sites before its complete digestion
within lysosomes. However, unlike its ligand, cycloheximide studies
indicated that internalized mIL-3 receptors are recycled to the cell
surface. When B6SUtA1 cells were continuously passaged in mIL-3, cell
populations allowed to exhaust the mIL-3 in the medium (high density cells)
expressed more than ten times (ie, approximately 100,000/cell) the mIL-3
receptor number of those growing exponentially at low cell concentrations
(low density cells). Since the high density cells were no larger than the
low density cells, the marked increase in mIL-3 receptor number per cell
reflects a true up-regulation of receptor expression. A kinetic analysis of
this up- regulation revealed that it begins within one hour of mIL-3
exhaustion. Moreover, proliferation assays with these two cell populations,
using 3H-thymidine incorporation, suggested that the high density cells
were 30-fold more responsive to mIL-3. However, when B6SUtA1 cells were
passaged in mGM-CSF, there was no difference in mIL-3 receptor number
between high density and low density cells (ie, approximately
100,000/cell). Identical studies carried out with another mIL-3 dependent
cell line, 32D C3, demonstrated that this phenomenon was not unique to
B6SUtA1 cells.
Volume 73,
Issue 5,
pp. 1180-1187,
04/01/1989
Copyright © 1989 by The American Society of Hematology
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