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Insulin-like growth factor-1 potentiates expansion of interleukin-7-
dependent pro-B cells
LF Gibson, D Piktel and KS Landreth
Department of Pediatrics, West Virginia University Health Sciences Center,
Morgantown 26506.
Commitment to B-lymphocyte differentiation is characterized by expression
of the B220 form of the common leukocyte antigen (Ly-5) and D-JH
rearrangement of the Ig heavy chain gene complex. B-lineage progenitor
cells, or pro-B cells, that have initiated Ig gene rearrangement, but do
not express detectable Ig heavy or light chain protein, have recently been
shown to retain substantial capacity for expansion in vitro in the presence
of bone marrow (BM) stromal cells and interleukin-7 (IL-7). Although the
potentiating effect of stromal cells on pro-B-cell proliferation can be
partially attributed to the ligand for the proto-oncogene receptor c-kit
(c-kit ligand [KL] or stem cell factor), several lines of evidence suggest
that c-kit-mediated cell signalling is not required for pro-B-cell
expansion. Previous studies from this laboratory demonstrated that
insulin-like growth factor-1 (IGF-1) potentiated the proliferative effect
of IL-7 on nonadherent cells from lymphoid long-term BM cultures in a
manner similar to that shown for KL. To further delineate specific cell
stages that respond to lymphopoietic cytokines, we derived continuously
proliferating pro-B-cell lines from day-14 murine fetal liver in the
presence of IL-7 and BM stromal cell clone S10. Initial expansion and
continued proliferation of these pro-B-cell lines was absolutely dependent
on the presence of both IL-7 and stromal cells. In the absence of KL,
IL-7-stimulated proliferation of these cells in short- term cultures and
addition of either recombinant IGF-1 or KL significantly potentiated this
proliferative response. Although IGF-2 and insulin also potentiated the
effect of IL-7, our data suggest that neither IGF-2 nor insulin represent
normal regulators of intramyeloid lymphocyte development. IGF-1 and KL
activate unique cascades of intracellular signalling events and inclusion
of both cytokines in cultures of IL-7-stimulated pro-B cells resulted in
additive potentiation of the proliferative response. Taken together, these
results suggest that expansion of pro-B cells in vivo is maintained by at
least three stromal cell-derived cytokines. IL-7 appears to be unique in
delivering the primary proliferative signal for pro-B-cell expansion;
however, both KL and IGF-1 potentiate the proliferative effect of IL-7 on
these cells. The functional redundancy and additive effects of IGF-1 and KL
as amplification signals for developing B- lineage cells underscore the
essential nature of clonal expansion and diversification in development of
immunocompetent lymphoid cells.
Volume 82,
Issue 10,
pp. 3005-3011,
11/15/1993
Copyright © 1993 by The American Society of Hematology
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