Faquin W C, Schneider T J, Goldberg M A
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Blood. 1992 Apr 15;79(8):1987-94.
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.
研究了炎性细胞因子白细胞介素-1α（IL-1α）、IL-1β、IL-6、转化生长因子-β（TGF-β）和肿瘤坏死因子-α（TNF-α）对Hep3B细胞中促红细胞生成素（Epo）产生的影响。添加IL-1α、IL-1β或TNF-α会导致对缺氧诱导的Epo产生呈剂量依赖性抑制，抑制程度高达89%。IL-1β是所测试的最有效的细胞因子，在0.4 U/mL时表现出半数最大抑制，而IL-1α和TNF-α分别在1.0 U/mL和10.0 U/mL时表现出半数最大抑制。TGF-β也抑制缺氧诱导的Epo产生，但仅高达56%。与IL-1α、IL-1β、TNF-α和TGF-β相反，向缺氧的Hep3B细胞中添加IL-6会导致对缺氧诱导的Epo产生呈剂量依赖性刺激，刺激程度高达81%。然而，在没有缺氧的情况下，IL-6不会刺激Epo合成，因此在诱导Epo产生方面与缺氧具有协同作用。发现IL-1α、TNF-α和IL-6的组合对缺氧诱导的Epo产生的影响具有相加性。通过Northern印迹分析，当同时暴露于IL-1α或TNF-α时，在1% O2中生长的Hep3B细胞中的Epo信使RNA水平会降低。IL-1α、IL-1β、TGF-β、TNF-α和IL-6对缺氧诱导的Epo产生的影响可能为缺氧导致基因表达变化的信号转导途径提供新的见解。此外，这些炎性细胞因子对体外缺氧诱导的Epo产生的影响表明，在各种炎性疾病中，这些细胞因子可能会影响体内Epo的产生，并可能在慢性病贫血的发病机制中起重要作用。
