title: High-fat diet activates pro-inflammatory response in the prostate through association of Stat-3 and NF-κB.
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.
authors: Department of Urology, Case Western Reserve University & The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors: Eswar
authors: E
authors: Shankar
authors: Eugene V
authors: EV
authors: Vykhovanets
authors: Olena V
authors: OV
authors: Vykhovanets
authors: Gregory T
authors: GT
authors: Maclennan
authors: Rajesh
authors: R
authors: Singh
authors: Natarajan
authors: N
authors: Bhaskaran
authors: Sanjeev
authors: S
authors: Shukla
authors: Sanjay
authors: S
authors: Gupta
references: Curr Biol. 1999 Jun 3;9(11):601-4
references: 10359702
references: Curr Diab Rep. 2009 Feb;9(1):26-32
references: 19192421
references: Mol Cancer. 2009 Feb 19;8:9
references: 19228372
references: Obesity (Silver Spring). 2009 Oct;17(10):1866-71
references: 19543212
references: Nat Rev Cancer. 2009 Nov;9(11):798-809
references: 19851315
references: Mol Cancer. 2010 Apr 30;9:97
references: 20433747
references: Nature. 2007 May 31;447(7144):525-7
references: 17538594
references: Prostate. 2011 Oct 1;71(14):1499-509
references: 21374652
references: J Urol. 2009 Dec;182(6 Suppl):S1
references: 19846132
references: Cancer Res. 2007 Sep 15;67(18):8828-38
references: 17875724
references: J Clin Invest. 2007 Mar;117(3):739-45
references: 17318260
references: J Biol Chem. 2006 Aug 11;281(32):22799-807
references: 16785234
references: Prostate. 2011 Feb 1;71(2):147-56
references: 20632379
references: Am J Respir Cell Mol Biol. 1997 Jul;17(1):3-9
references: 9224203
references: Nature. 2006 Dec 14;444(7121):860-7
references: 17167474
references: J Immunol. 2004 May 15;172(10):6336-44
references: 15128824
references: J Biol Chem. 1999 Oct 22;274(43):30353-6
references: 10521409
references: Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11924-9
references: 20547855
references: Curr Diabetes Rev. 2006 May;2(2):195-211
references: 18220627
references: Br J Nutr. 2010 May;103(9):1375-80
references: 20082736
references: Cell. 1995 Jul 28;82(2):241-50
references: 7543024
references: J Exp Med. 2009 Jul 6;206(7):1457-64
references: 19564351
references: Genes Dev. 2007 Jun 1;21(11):1396-408
references: 17510282
references: Ann N Y Acad Sci. 2009 Aug;1171:59-76
references: 19723038
references: FASEB J. 2005 Dec;19(14):2042-4
references: 16230333
references: EMBO J. 1995 Apr 3;14(7):1421-9
references: 7537214
references: J Neuroinflammation. 2010 Mar 06;7:16
references: 20205746
references: Genes Nutr. 2009 Sep;4(3):215-22
references: 19707810
references: Trends Mol Med. 2008 Mar;14(3):109-19
references: 18261959
references: Endocrinology. 2005 Oct;146(10):4192-9
references: 16002529
references: Prostate. 2009 May 1;69(6):633-43
references: 19170127
references: EMBO Rep. 2009 Dec;10(12):1314-9
references: 19893576
references: Nature. 1999 Sep 2;401(6748):86-90
references: 10485711
references: J Biol Chem. 1999 Aug 20;274(34):24392-400
references: 10446219
references: Diabetologia. 2009 Dec;52(12):2616-20
references: 19809797
references: J Immunol. 2003 Jun 1;170(11):5630-5
references: 12759443
references: Cancer Cell. 2009 Apr 7;15(4):283-93
references: 19345327
references: J Biol Chem. 2003 Sep 19;278(38):36916-23
references: 12842894
references: Am J Pathol. 1999 Dec;155(6):1985-92
references: 10595928
references: Clin Cancer Res. 2005 Nov 1;11(21):7674-82
references: 16278387
references: Nat Rev Immunol. 2009 Nov;9(11):778-88
references: 19855404