Interleukin-1β inhibits the hypoxic inducibility of the erythropoietin enhancer by suppressing hepatocyte nuclear factor-4α

Abstract

The suppression of hypoxia-induced erythropoietin (EPO) expression by inflammatory cytokines like interleukin-1 (IL-1) contributes to the development of the anemia of chronic disease (ACD). However, the precise mechanism of this suppression is unclear. The 3'-EPO enhancer mediates the transcriptional response to hypoxia by binding several transcription factors, including hypoxia-inducible factor, hepatocyte nuclear factor-4alpha (HNF-4alpha) and chicken ovalbumin upstream promoter transcription factor. We investigated whether IL-1beta inhibits the activity of the 3'-EPO enhancer via HNF-4alpha. IL-1beta inhibited HNF-4alpha mRNA expression and caused proteasome-dependent degradation of HNF-4alpha protein, which resulted in a strongly reduced DNA-binding activity of HNF-4alpha. Reporter gene assays revealed that IL-1beta caused a complete suppression of the hypoxic inducibility of the 3' enhancer via inhibition of HNF-4alpha. We conclude that IL-1beta, at least partially, reduces hypoxia-induced EPO expression by down-regulation of HNF-4alpha.

Regulation of erythropoietin production

“…The relative lack of Epo in patients with anaemia associated with chronic disease has been related to the negative effects of the cytokines interleukin‐1 (Il‐1) and tumour necrosis factor‐α on Epo expression (Jelkmann, 1998). In vitro , Il‐1 inhibits HNF‐4α mRNA formation and causes proteasome‐dependent degradation of HNF‐4α protein, thereby suppressing the hypoxic inducibility of the Epo enhancer (Krajewski et al 2007). The anaemias of patients with CKD or cancer in combination with chemotherapy can be corrected by replacement therapy with rhEpo or its analogues (see Macdougall & Ashenden, 2009).…”

Role of hepcidin‐ferroportin axis in the pathophysiology, diagnosis, and treatment of anemia of chronic inflammation

“…The pathophysiology of ACI is multifactorial, resulting from the effects of inflammatory cytokines such as TNF‐α, interferon‐γ, and IL‐1 which suppress erythroid precursor differentiation and erythropoietin responsiveness, impeding the bone marrow's ability to compensate for enhanced erythrophagocytosis by cytokine‐activated splenic macrophages. In addition, inflammation may also influence erythropoietin production and renal excretion of hepcidin . However, there is now some consensus that ACI is in large part a consequence of altered iron metabolism resulting from the immune modulation of an underlying chronic disease in which immune mediators, such as IL‐6 and possibly other cytokines involved in host defense, lead to hepcidin‐induced hypoferremia, resulting in iron sequestration within the reticuloendothelial system, decreasing iron availability for erythropoiesis (Table ).…”

Obesity, anemia, and cardiovascular risk in patients with chronic kidney disease: Overview and pathophysiologic insights

“…In patients with rheumatoid arthritis, rheumatoid arthritis-associated anemia, IL-1β, IL-6, and TNF-α concentrations have been found to inhibit erythroid blast-forming units and erythroid colony-forming units in patients with anemia of chronic disease and in healthy controls [41]. IL-1β has been shown to inhibit activation of the 3′-EPO enhancer by inhibiting the hepatocyte nuclear factor-4α (HNF-4α) mRNA expression and causing proteosome-dependent degradation of the HNF-4α protein, which act in concert to strongly decrease the DNA binding activity of HNF-4α [44]. In this way, IL-1β completely suppressed the hypoxic inducibility of the 3′ enhancer by inhibiting HNF-4α [44].…”

“…IL-1β has been shown to inhibit activation of the 3′-EPO enhancer by inhibiting the hepatocyte nuclear factor-4α (HNF-4α) mRNA expression and causing proteosome-dependent degradation of the HNF-4α protein, which act in concert to strongly decrease the DNA binding activity of HNF-4α [44]. In this way, IL-1β completely suppressed the hypoxic inducibility of the 3′ enhancer by inhibiting HNF-4α [44]. IL-1β and TNF-α also have been shown to inhibit EPO promoter activity by increasing the binding activity of GATA [45].…”