Interleukin-4 induces a substance in bone marrow stromal cells that
reversibly inhibits factor-dependent and factor-independent cell
proliferation
C Peschel, I Green and WE Paul
Laboratory of Immunology, National Institute of Allergy and Infectious
Diseases, Bethesda, MD 20892.
Bone marrow-derived stromal cell monolayers pretreated with recombinant
interleukin-4 (IL-4) inhibit the growth of hematopoietic cells. This was
demonstrated by inhibition of fresh bone marrow-derived, IL-3- induced soft
agar colonies as well as by inhibition of proliferation of IL-3-dependent
cell lines and of a Friend virus-transformed erythroleukemic cell line.
Pretreatment of stromal cells with IL-4 for five to seven days induced the
inhibitory activity. IL-4 could then be removed before "plating" the bone
marrow cells in soft agar, indicating that the inhibitory activity did not
depend on the action of IL-4 on the precursors of the soft agar colonies.
The inhibitory activity appears to be mediated by a soluble factor since
inhibition was achieved even if the stromal cell layer was separated from
the colony forming cells by an "empty" agar layer. However, supernatants of
IL-4- induced stromal cell layers had no detectable inhibitory activity.
The inhibitory action of the IL-4-pretreated stromal cell lines was not the
result of killing of the precursor cells since it could be reversed if the
agar layer containing the colony-forming cells was removed from the stromal
cell layer and cultured with IL-3. Hydrocortisone (HC) blocked the
inhibitory effect if added either in the IL-4 preincubation phase or during
the colony formation stage, implying that HC blocked both induction of the
inhibitory activity and its release or its effector function. A homogenous
long-term stromal cell line could not be induced to exert the inhibitory
activity; partial inhibition could be achieved with pure macrophages
stimulated with IL-4 and CSF-1, suggesting that the inhibitory activity
induced by IL-4 in mixed stromal cell layers may depend on a complex
mechanism involving more than one cell type. Northern analysis of RNA from
IL-4-induced and uninduced stromal cells indicated that IL-4 did not
upregulate expression of CSF-1 or transforming growth factor-beta
(TGF-beta) and only modestly increased expression of tumor necrosis factor,
suggesting that these cytokines were not responsible for the inhibitory
activity. The capacity of IL-4 to induce inhibitory activity in stromal
cell layers suggests that IL-4 may play a role in the regulation of
hematopoiesis.
Volume 73,
Issue 5,
pp. 1130-1141,
04/01/1989
Copyright © 1989 by The American Society of Hematology
