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Hematopoietic inhibition by interferon-gamma is partially mediated through
interferon regulatory factor-1
T Sato, C Selleri, NS Young and JP Maciejewski
Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, MD
20892-1652, USA.
Biologic responses to cytokines are mediated by intracellular pathways
involving induction of signaling and metabolic cascades. Interferon (IFN)
regulatory factor-1 (IRF-1) is a major transcription factor induced not
only by IFN-gamma but also by other cytokines including tumor necrosis
factor-alpha (TNF-alpha). Possible IRF-1 binding sequence elements have
been located in the promoter regions of several genes, including p53,
inducible nitric oxide synthase, and cyclin D1. IFN-gamma and TNF-alpha can
inhibit hematopoiesis in vitro and have been implicated in the
pathophysiology of bone marrow (BM) failure. We investigated whether the
inhibitory effects of these cytokines were intracellularly mediated through
the expression of IRF-1 or -2 in target cells. In total BM cells, IRF-1
mRNA expression increased after stimulation with IFN-gamma and TNF-alpha;
the stronger effect was observed with IFN-gamma. In contrast, IRF-2 mRNA
expression was constitutive and not altered by cytokine stimulation. By
gene amplification, low levels of IRF-1 mRNA were present in unstimulated,
highly purified CD34+ cells; on exposure to IFN-gamma and TNF-alpha,
amplified IRF-1 mRNA showed a much stronger signal than control. When CD34+
cells were treated with IFN-gamma and TNF-alpha, IRF-1 antisense
oligodeoxynucleotide (ODN) partially reversed the suppressive effects on
CD34+ cell-derived colony formation by IFN-gamma but not those by
TNF-alpha. In parallel experiments, IRF-1 antisense ODN decreased both
IRF-1 protein and mRNA expression. The effects of ODN were sequence-
specific and concentration-dependent. These results suggest that the
inhibitory hematopoietic effects of IFN-gamma and TNF-alpha are mediated by
different pathways. For IFN-gamma, IRF-1 is involved in the activation of
cellular genes responsible for IFN-gamma suppressive effects.
Volume 86,
Issue 9,
pp. 3373-3380,
11/01/1995
Copyright © 1995 by The American Society of Hematology
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