Peroxisome Proliferator-Activated Receptor Delta Agonists and AMP-Activated Protein Kinase Activators Reverse Interleukin 6-Inhibited Erythropoietin Receptor Expression

Abstract

BACKGROUND: Interleukin-6 (IL-6) was shown to inhibit erythropoietin receptor (EpoR) expression in erythroid progenitor cells. The anti-inflammatory effects of peroxisome proliferator-activated receptor (PPAR) agonists and AMP-activated protein kinase (AMPK) activators have been proven in previous studies. This study is going to evaluate the effects of PPAR agonists and AMPK activators on IL-6- induced inhibition of EpoR expression and possible mechanisms. METHODS: Human erythroleukemia cells (K562) were incubated with IL-6 (5 ng/mL) for 18 hours in the presence and then absence of an AMPK activator HybriMore (200 μM) and peroxisome proliferatoractivated receptor δ (PPARδ) agonists L-165,041 (1 μM). The expression of EpoR and two downstream substances of AMPK, phosphorylated acetyl-CoA carboxylase (ACC), and glycogen synthase kinase (GSK) in K562 cells was measured. RESULTS: IL-6 significantly inhibited EpoR expression in K562 cells. HybriMore (200 μM) and L-165,041 (1 μM) significantly reversed IL-6 induced inhibition of EpoR expression with similar potency. IL-6 also significantly inhibited phosphorylated glycogen synthase kinase 3 (GSK3) and ACC expression. HybriMore showed no effect on IL-6-induced inhibition of phosphorylated GSK3 and ACC. L-165,041, however, reversed the inhibition of ACC, but had no effect on GSK3. CONCLUSION: Both PPAR agonists and AMPK activators significantly reverse IL-6-inhibited EpoR expression in K562 cells. The effect of AMPK activators may have no relationship with ACC or GSK3.