REGULATION OF CYTOKINE EXPRESSION BY INTERFERON-ALPHA IN HUMAN BONE-MARROW STROMAL CELLS - INHIBITION OF HEMATOPOIETIC GROWTH-FACTORS AND INDUCTION OF INTERLEUKIN-1 RECEPTOR ANTAGONIST

We investigated the effects of interferon-alpha (IFN-alpha) on the expression of cytokines by human bone marrow stromal cells, Production of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-CSF (G-CSF), and interleukin-1 beta (IL-1 beta) in stromal cell layers was induced by incubation with IL-1 alpha, tumor necrosis factor (TNF), or lipopolysaccharide (LPS). Addition of IFN-alpha to such stimulated cultures resulted in a strong downregulation of mRNA expression of GM-CSF and IL-1 beta. Similarly, the protein levels of GM-CSF and IL-1 beta were significantly reduced by IFN-alpha, whereas G-CSF production was only moderately inhibited. In contrast, IFN-alpha markedly stimulated the production of IL-1 receptor antagonist (IL-1RA) by stromal cells, The inhibition of cytokine expression resulted in a reduced hematopoietic activity of stromal cells, indicated by a reduced proliferation of the factor dependent cell line MO7e on IFN-alpha-treated stromal cells, In the presence of cycloheximide (CHX), IFN-alpha failed to inhibit IL-l mRNA expression, whereas the regulation of GM-CSF and IL-1RA by IFN-alpha was not affected, Our results indicate that the myelosuppressive effects of IFN-alpha, as observed in therapeutic applications or associated with viral infections, are, in part, indirectly mediated by inhibition of the paracrine production of hematopoietic growth factors. (C) 1994 by The American Society of Hematology.