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Departments of
*
Internal Medicine and
Pathology, Virginia Commonwealth University, Richmond, VA 23298; and
Department of Metabolic Diseases, Hoffman-LaRoche Inc., Nutley, NJ 07110
Although stem cell factor (SCF) appears to be the major
growth factor for human mast cells, other factors undoubtedly play
important roles in the development, survival, and function of these
cells. The current study examined the effects of recombinant human (rh)
IL-4 and rhIL-6 on rhSCF-dependent development and survival of human
mast cells derived in vitro from cord blood progenitor cells. After
4–8 wk of culture with rhSCF and various amounts of rhIL-4, a dramatic
decline in mast cell numbers was observed with rhIL-4, the
EC50 being about 0.1 ng/ml. Numbers of other cell types
remained high. Mast cells derived from cord blood progenitors after 7
wk of culture with rhSCF alone displayed an MCT phenotype
and expressed Kit, Fc
RI, and IL-4R on their surface. Mast cells
examined after purification by immunomagnetic sorting became apoptotic
within hours after exposure to rhIL-4, a phenomenon blocked by
anti-IL-4 Ab. Because rhIL-4-dependent apoptosis but not the loss
of mitochondrial membrane potential was prevented by the pan-caspase
inhibitor benzyloxycarbonyl-Val-Ala-Asp-(Z-VAD)-fluoromethylketone,
mitochondrial perturbation most likely preceded caspase activation.
Consistent with this conclusion was the observation that both apoptosis
and loss of mitochondrial membrane potential (
m) were
inhibited by cyclosporin A in combination with aristolochic acid.
rhIL-6 protected cord blood mast cells from rhIL-4-induced apoptosis.
Thus, IL-4 can cause both maturation and apoptosis of human mast cells,
the latter effect being abrogated by IL-6.
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