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 exp ression of cytokines by human bone marrow stromal cells, Production of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyt e-CSF (G-CSF), and interleukin-1 beta (IL-1 beta) in stromal cell laye rs was induced by incubation with IL-1 alpha, tumor necrosis factor (T NF), or lipopolysaccharide (LPS). Addition of IFN-alpha to such stimul ated cultures resulted in a strong downregulation of mRNA expression o f 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 product ion was only moderately inhibited. In contrast, IFN-alpha markedly sti mulated the production of IL-1 receptor antagonist (IL-1RA) by stromal cells, The inhibition of cytokine expression resulted in a reduced he matopoietic activity of stromal cells, indicated by a reduced prolifer ation of the factor dependent cell line MO7e on IFN-alpha-treated stro mal 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 myel osuppressive effects of IFN-alpha, as observed in therapeutic applicat ions or associated with viral infections, are, in part, indirectly med iated by inhibition of the paracrine production of hematopoietic growt h factors. (C) 1994 by The American Society of Hematology.