Erythropoietin gene expression is suppressed after lipopolysaccharide or interleukin-1 beta injections in rats

Frede, Stilla; Fandrey, Joachim; Pagel, Horst; Hellwig, Thomas; Jelkmann, Wolfgang

doi:10.1152/ajpregu.1997.273.3.r1067

Cited by 65 publications

(58 citation statements)

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“…Consistent with reduced EPO production in LPStreated rats [30], the present study found downregulation of EPO gene and protein expression following LPS treatment in A549 cells. Potential mechanisms include inhibition of EPO gene expression by the transcription factor nuclear factor (NF)-kB [31], which is upregulated by LPS, or a secondary effect through induction of pro-inflammatory cytokines including interleukin-1b and tumour necrosis factor-a, which have also been shown to inhibit EPO gene and protein expression [32].…”

Section: Expression Of Epo and Epor Has Been Demonstrated In A Widesupporting

confidence: 87%

Erythropoietin inhibits respiratory epithelial cell apoptosis in a model of acute lung injury

MacRedmond¹,

Singhera²,

Dorscheid³

2009

Eur Respir J

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Fas-mediated apoptosis of the alveolar epithelium is important in the pathogenesis of acute respiratory distress syndrome. Erythropoietin (EPO) has cytoprotective properties in other organ systems, and is relatively deficient in critical illness. This study investigates a potential role for EPO in reducing apoptosis in a model of acute lung injury.Apoptosis was induced in human alveolar epithelial (A549) cells or normal human bronchial epithelial (NHBE) cells by Fas activation with CH-11 Fas-crosslinking antibody or by co-culture with polymorphonuclear neutrophils in a transwell system. The effect of recombinant human (rh)EPO on apoptosis was measured by poly(ADP-ribose) polymerase cleavage and cell death detection assay. The specific EPO-EPO receptor (EPOR)-mediated effect was determined using an EPO-blocking antibody or EPOR small interfering RNA.Expression of EPOR was demonstrated in A549, NHBE and normal human alveolar epithelium. Fas-and neutrophil-mediated apoptosis of A549 and NHBE cells was inhibited by rhEPO by a specific EPO-EPOR-mediated mechanism. This anti-apoptotic effect was associated with induction of a pro-apoptotic Bcl-xL/Bax ratio.EPO has cytoprotective properties in respiratory epithelium in an in vitro model, which may indicate a potential therapeutic role in acute lung injury.

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Section: Expression Of Epo and Epor Has Been Demonstrated In A Widesupporting

confidence: 87%

Erythropoietin inhibits respiratory epithelial cell apoptosis in a model of acute lung injury

MacRedmond¹,

Singhera²,

Dorscheid³

2009

Eur Respir J

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“…Inflammatory cytokines, such as TNFa, have been shown to repress hypoxia-responsive Epo-producing ability, 30,31 and are assumed to be key pathogenic regulators of anemia of chronic disease 32 and UUO-induced renal fibrosis. 18,19,33 In turn, TGFb/Smad signaling is the central pathway for myofibroblast activation and transformation.…”

Section: Discussionmentioning

confidence: 99%

Plasticity of Renal Erythropoietin-Producing Cells Governs Fibrosis

Souma¹,

Yamazaki²,

Moriguchi³

et al. 2013

Journal of the American Society of Nephrology

164

223

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CKD progresses with fibrosis and erythropoietin (Epo)-dependent anemia, leading to increased cardiovascular complications, but the mechanisms linking Epo-dependent anemia and fibrosis remain unclear. Here, we show that the cellular phenotype of renal Epo-producing cells (REPs) alternates between a physiologic Epo-producing state and a pathologic fibrogenic state in response to microenvironmental signals. In a novel mouse model, unilateral ureteral obstruction-induced inflammatory milieu activated NFkB and Smad signaling pathways in REPs, rapidly repressed the Epo-producing potential of REPs, and led to myofibroblast transformation of these cells. Moreover, we developed a unique Cre-based cell-fate tracing method that marked current and/or previous Epo-producing cells and revealed that the majority of myofibroblasts are derived from REPs. Genetic induction of NFkB activity selectively in REPs resulted in myofibroblastic transformation, indicating that NFkB signaling elicits a phenotypic switch. Reversing the unilateral ureteral obstruction-induced inflammatory microenvironment restored the Epo-producing potential and the physiologic phenotype of REPs. This phenotypic reversion was accelerated by anti-inflammatory therapy. These findings demonstrate that REPs possess cellular plasticity, and suggest that the phenotypic transition of REPs to myofibroblasts, modulated by inflammatory molecules, underlies the connection between anemia and renal fibrosis in CKD.

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“…Most of the in vivo studies performed till today focused mainly on the inhibitory effects of these cytokines on kidney EPO expression under hypoxic conditions. 34,35 The analysis of two models characterized by 36 The regulation of EPO gene expression during hypoxia has been widely explained, 37 but several points concerning the tissue-specific EPO gene expression and the after-birth switch between the fetal hepatic production and the adult kidney counterpart still need further clarifications. The HIF transcription factor family has been initially identified as the Figure 14 Mouse hepatocytes stimulation with IL-6 in normoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

Cellular and molecular mechanisms regulating the hepatic erythropoietin expression during acute-phase response: a role for IL-6

Ramadori

Ahmad

Ramadori

2010

Laboratory Investigation

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The source of circulating erythropoietin (EPO), the mediators and the mechanisms involved in the upregulation of EPO gene expression during acute-phase reaction are still poorly understood. Acute-phase reaction was induced by either intramuscular turpentine oil (TO) or intraperitoneal lipopolysaccharide (LPS) administration into wild-type and interleukin (IL)-6 knockout (KO) mice. Animals were killed at different time points and blood, liver and muscle tissue were collected. Serum levels of EPO were measured by enzyme-linked immunoadsorbent assay; liver and injured muscle samples were processed for RNA isolation and for protein analysis. EPO, hypoxia-inducible factors 1a and 2a (HIF-1a and HIF-2a) mRNA were analyzed by RT-PCR and the protein levels were analyzed by western blot and electrophoretic mobility shift assay. HIF-1a and HIF-2a localization was performed through immunofluorescence staining. EPO, HIF-1 and HIF-2 gene and protein expression levels were also analyzed in isolated mouse hepatocytes after stimulation with IL-6. In the wild-type animals, EPO serum levels increased dramatically at 12 h after the insults together with the hepatic gene expression. In TO-treated animals, the EPO gene expression reached an 8.2-fold increase at 12 h, and in LPS-treated mice a similar induction was recorded at 6 h (about 4.5-fold increase). In the IL-6KO strain, the upregulation after the inflammatory stimuli was much lower (only 2.0-fold increase). A progressive upregulation of HIF-1a and HIF-2a was detectable until 6 h after the insults, but only HIF-1a upregulation was reduced in IL-6KO mice. In isolated hepatocytes, stimulation with a single dose of IL-6 induced a nuclear accumulation of HIF-1a, in parallel with an increase of EPO mRNA. No effect on HIF-2a expression was found. IL-6 appears to be the main regulator of EPO gene expression and a major contributor for HIF-1a induction in hepatocytes and Kupffer cells during acute-phase response. The increase of HIF-2a, predominantly expressed in endothelial cells and fibroblast-like cells, seems not to be affected by the lack of IL-6.

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Erythropoietin gene expression is suppressed after lipopolysaccharide or interleukin-1 beta injections in rats

Cited by 65 publications

References 0 publications

Erythropoietin inhibits respiratory epithelial cell apoptosis in a model of acute lung injury

Erythropoietin inhibits respiratory epithelial cell apoptosis in a model of acute lung injury

Plasticity of Renal Erythropoietin-Producing Cells Governs Fibrosis

Cellular and molecular mechanisms regulating the hepatic erythropoietin expression during acute-phase response: a role for IL-6

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