Effect of inflammatory cytokines on hypoxia-induced erythropoietin production

Abstract

The effects of the inflammatory cytokines interleukin-1α (IL-1α) IL-1β, IL-6, transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) on erythropoietin (Epo) production in Hep3B cells were examined. The addition of IL-1α, IL-1β or TNF-α resulted in a dose-dependent inhibition of hvpoxia-induced Epo production by as much as 89%. IL-1β 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-1α and TNF-α, respectively. TGF-β also inhibited hypoxia-induced Epo production, but only by as much as 56%. In contrast to IL-1α, IL-1β, TNF-α, and TGF-β, 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-1α, TNF-α, 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-1α or TNF-α. The effects that IL-1α, IL-1β, TGF-β, TNF-α, 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. © 1992 by The American Society of Hematology.