Regulation of cytokine expression by interferon-α in human bone marrow stromal cells: Inhibition of hematopoietic growth factors and induction of interleukin-1 receptor antagonist

We investigated the effects of interferon-α (IFN-α) 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-1β (IL-1β) in stromal cell layers was induced by incubation with IL-1α, tumor necrosis factor (TNF), or lipopolysaccharide (LPS). Addition of IFN-α to such stimulated cultures resulted in a strong downregulation of mRNA expression of GM-CSF and IL-1β. Similarly, the protein levels of GM-CSF and IL-1β were significantly reduced by IFN-α, whereas G-CSF production was only moderately inhibited. In contrast, IFN-α 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-α-treated stromal cells. In the presence of cycloheximide (CHX), IFN-α failed to inhibit IL-1 mRNA expression, whereas the regulation of GM-CSF and IL-1RA by IFN-α was not affected. Our results indicate that the myelosuppressive effects of IFN-α, 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.