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-1 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.
Aman
M J
MJ
Third Department of Medicine, Johannes Gutenberg University School of Medicine, Mainz, Germany.
Keller
U
U
Derigs
G
G
Mohamadzadeh
M
M
Huber
C
C
Peschel
C
C
D001483:Base Sequence; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D002460:Cell Line; D002478:Cells, Cultured; D003238:Connective Tissue / Q000187:drug effects* / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006410:Hematopoiesis / Q000187:drug effects; D016298:Hematopoietic Cell Growth Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D053590:Interleukin 1 Receptor Antagonist Protein; D008969:Molecular Sequence Data; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D016298:Hematopoietic Cell Growth Factors; C507763:IL1RN protein, human; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D003513:Cycloheximide