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Effect of inflammatory cytokines on hypoxia-induced erythropoietin
production
WC Faquin, TJ Schneider and MA Goldberg
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
The effects of the inflammatory cytokines interleukin-1 alpha (IL-1 alpha),
IL-1 beta, IL-6, transforming growth factor-beta (TGF-beta), and tumor
necrosis factor-alpha (TNF-alpha) on erythropoietin (Epo) production in
Hep3B cells were examined. The addition of IL-1 alpha, IL- 1 beta, or
TNF-alpha resulted in a dose-dependent inhibition of hypoxia- induced Epo
production by as much as 89%. IL-1 beta was the most effective cytokine
tested, demonstrating half-maximal inhibition at 0.4 U/mL compared with 1.0
and 10.0 U/mL for IL-1 alpha and TNF-alpha, respectively. TGF-beta also
inhibited hypoxia-induced Epo production, but only by as much as 56%. In
contrast to IL-1 alpha, IL-1 beta, TNF- alpha, and TGF-beta, the addition
of IL-6 to hypoxic Hep3B cells resulted in a dose-dependent stimulation of
hypoxia-induced Epo production by as much as 81%. However, IL-6 did not
stimulate Epo synthesis in the absence of hypoxia, and was thus synergistic
with hypoxia in inducing Epo production. Combinations of IL-1 alpha, TNF-
alpha, and IL-6 were found to be additive in their effects on hypoxia-
induced Epo production. By Northern blot analysis, Epo messenger RNA levels
in Hep3B cells grown in 1% O2 were decreased when concurrently exposed to
either IL-1 alpha or TNF-alpha. The effects that IL-1 alpha, IL-1 beta,
TGF-beta, TNF-alpha, and IL-6 have on hypoxia-induced Epo production may
provide new insights into the signal transduction pathway by which hypoxia
leads to changes in gene expression. In addition, the effects of these
inflammatory cytokines on hypoxia- induced Epo production in vitro suggest
that in various inflammatory disorders these cytokines may affect Epo
production in vivo and may play a significant role in the pathogenesis of
the anemia of chronic disease.
Volume 79,
Issue 8,
pp. 1987-1994,
04/15/1992
Copyright © 1992 by The American Society of Hematology
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