Interleukin-4 induces a substance in bone marrow stromal cells that reversibly inhibits factor-dependent and factor-independent cell proliferation.
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.
Peschel
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Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
Green
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Paul
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology; D001685:Biological Factors / Q000096:biosynthesis; D001853:Bone Marrow / Q000378:metabolism* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002474:Cell-Free System; D003114:Colony-Forming Units Assay; D003115:Colony-Stimulating Factors / Q000502:physiology*; D016207:Cytokines; D005109:Extracellular Matrix / Q000378:metabolism* / Q000502:physiology; D006131:Growth Inhibitors / Q000096:biosynthesis* / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects; D006854:Hydrocortisone / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C
D000911:Antibodies, Monoclonal; D001685:Biological Factors; D003115:Colony-Stimulating Factors; D016207:Cytokines; D006131:Growth Inhibitors; D007375:Interleukin-1; D007378:Interleukins; D015847:Interleukin-4; D007371:Interferon-gamma; D006854:Hydrocortisone