High‐fat diet activates pro‐inflammatory response in the prostate through association of Stat‐3 and NF‐κB

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Abstract
BACKGROUND: Signal transducer and activator of transcription (Stat)‐3 and nuclear factor‐kappa B (NF‐κB) are important signaling pathways constitutively activated during inflammation. We previously reported that high‐fat diet (HFD) intake induces oxidative stress in the prostate through elevated expression of NADPH oxidase subunits causing NF‐κB activation. We sought to determine whether Stat‐3 is involved in the activation of NF‐κB in the prostate as a result of HFD feeding, leading to inflammation.METHODS: C57BL/6 mice were either fed with regular diet (RD) or HFD for 4 and 8 weeks. Plasma cytokine levels were determined by multiplex analysis. Western blotting was performed to determine the expression of NF‐κB, Stat‐3, Akt, PDK1, PKCε, and their phosphorylated forms along with pathologic evaluation of the prostate. Immunoprecipitation and electrophoretic mobility shift assay (EMSA) were conducted to study the association between Stat‐3 and NF‐κB.RESULTS: C57BL/6 mice fed with HFD showed a significant increase in the plasma levels of IL‐1ß, IL‐6, IL‐17, and TNFα after 4 and 8 weeks of feeding, compared with RD controls. HFD feeding elevated the intraprostatic expression of IL‐6 and caused activation of PKCε and Akt, the upstream kinase regulating Stat‐3 and NF‐κB. Nuclear extracts from the prostates of mice fed with HFD exhibited constitutively activated levels of Stat‐3 and NF‐κB/p65. Increased association between the activated forms of Stat‐3 and NF‐κB/p65 was observed in the nucleus as a result of HFD feeding, a finding that was accompanied by morphologic evidence of increased intraprostatic inflammation.CONCLUSIONS: Our findings suggest that HFD activates Stat‐3 and NF‐κB/p65 in the prostate, and their interaction is associated with increased inflammation in the prostate. Prostate 72:233–243, 2012.
Funding Information
  • United States Public Health Services (NCI RO1CA108512, NCCAM RO1AT002709, NIDDK P20DK090871)
  • Sullivan Foundation for the Study of Prostatitis

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