title: Up-regulation of intestinal epithelial cell derived IL-7 expression by keratinocyte growth factor through STAT1/IRF-1, IRF-2 pathway.
abstract: BACKGROUND
  Epithelial cells(EC)-derived interleukin-7 (IL-7) plays a crucial role in control of development and homeostasis of neighboring intraepithelial lymphocytes (IEL), and keratinocyte growth factor (KGF) exerts protective effects on intestinal epithelial cells and up-regulates EC-derived IL-7 expression through KGFR pathway. This study was to further investigate the molecular mechanism involved in the regulation of IL-7 expression by KGF in the intestine.
  
  
  METHODS
  Intestinal epithelial cells (LoVo cells) and adult C57BL/6J mice were treated with KGF. Epithelial cell proliferation was studied by flow cytometry for BrdU-incorporation and by immunohistochemistry for PCNA staining. Western blot was used to detect the changes of expression of P-Tyr-STAT1, STAT1, and IL-7 by inhibiting STAT1. Alterations of nuclear extracts and total proteins of IRF-1, IRF-2 and IL-7 following IRF-1 and IRF-2 RNA interference with KGF treatment were also measured with western blot. Moreover, IL-7 mRNA expressions were also detected by Real-time PCR and IL-7 protein level in culture supernatants was measured by enzyme linked immunosorbent assay(ELISA).
  
  
  RESULTS
  KGF administration significantly increased LoVo cell proliferation and also increased intestinal wet weight, villus height, crypt depth and crypt cell proliferation in mice. KGF treatment led to increased levels of P-Tyr-STAT1, RAPA and AG490 both blocked P-Tyr-STAT1 and IL-7 expression in LoVo cells. IRF-1 and IRF-2 expression in vivo and in vitro were also up-regulated by KGF, and IL-7 expression was decreased after IRF-1 and IRF-2 expression was silenced by interfering RNA, respectively.
  
  
  CONCLUSIONS
  KGF could up-regulate IL-7 expression through the STAT1/IRF-1, IRF-2 signaling pathway, which is a new insight in potential effects of KGF on the intestinal mucosal immune system.
authors.affiliation: Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yu-Jiao
authors.initials: YJ
authors.lastname: Cai
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Sun
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Teitelbaum
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D051523:Fibroblast Growth Factor 7 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects / Q000502:physiology; D050856:Interferon Regulatory Factor-1 / Q000276:immunology / Q000378:metabolism*; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; C508605:IL7 protein, human; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D015851:Interleukin-7; C494258:Irf1 protein, mouse; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D051523:Fibroblast Growth Factor 7
references.citation: Cell. 1989 Aug 25;58(4):729-39
references.pmid: 2475256
references.citation: Curr Opin Immunol. 1995 Apr;7(2):206-13
references.pmid: 7546380
references.citation: J Clin Invest. 1995 Jun;95(6):2945-53
references.pmid: 7769137
references.citation: Exp Eye Res. 1994 Dec;59(6):665-78
references.pmid: 7698260
references.citation: Invest Ophthalmol Vis Sci. 1998 Jul;39(8):1329-38
references.pmid: 9660480
references.citation: Mol Cell Biol. 1999 Jan;19(1):431-40
references.pmid: 9858567
references.citation: J Clin Invest. 1994 Nov;94(5):1764-77
references.pmid: 7962522
references.citation: J Immunol. 2001 Aug 15;167(4):1954-61
references.pmid: 11489975
references.citation: Dev Dyn. 1995 Jun;203(2):223-40
references.pmid: 7655084
references.citation: Immunity. 1998 Feb;8(2):157-66
references.pmid: 9491997
references.citation: Gut. 1998 Nov;43(5):620-8
references.pmid: 9824341
references.citation: Blood. 2002 Jun 15;99(12):4592-600
references.pmid: 12036893
references.citation: Mech Dev. 1994 Jan;45(1):15-30
references.pmid: 8186145
references.citation: Invest Ophthalmol Vis Sci. 1991 Feb;32(2):336-40
references.pmid: 1993585
references.citation: Proc Natl Acad Sci U S A. 1989 Feb;86(3):802-6
references.pmid: 2915979
references.citation: Dig Dis Sci. 1995 Aug;40(8):1744-9
references.pmid: 7648974
references.citation: Science. 1989 Aug 18;245(4919):752-5
references.pmid: 2475908
references.citation: Int J Clin Exp Pathol. 2012;5(6):569-80
references.pmid: 22949940
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8732-7
references.pmid: 11447288
references.citation: Mol Immunol. 2007 Apr;44(11):2923-32
references.pmid: 17300840
references.citation: Cytokine. 2005 Sep 21;31(6):419-28
references.pmid: 16102972
references.citation: Blood. 2002 Nov 1;100(9):3269-78
references.pmid: 12384427
references.citation: Cancer. 2005 Mar 1;103(5):1054-63
references.pmid: 15651075
references.citation: Immunity. 2008 Oct 17;29(4):565-77
references.pmid: 18848473
references.citation: J Immunol. 2001 Mar 1;166(5):3019-27
references.pmid: 11207251
references.citation: Science. 1994 Jun 3;264(5164):1415-21
references.pmid: 8197455
references.citation: Cancer Res. 2003 Aug 1;63(15):4472-80
references.pmid: 12907620
references.citation: J Immunol. 1996 May 15;156(10):3806-14
references.pmid: 8621917
references.citation: Mol Cell Biol. 2004 Jul;24(14):6298-310
references.pmid: 15226432
references.citation: Nature. 1996 Feb 15;379(6566):645-8
references.pmid: 8628398
references.citation: Dev Biol. 1993 Aug;158(2):475-86
references.pmid: 8393815
references.citation: J Immunol. 1997 Jun 1;158(11):5393-9
references.pmid: 9164960
references.citation: Cancer Res. 1998 Mar 1;58(5):933-9
references.pmid: 9500453
references.citation: Mol Cell Biol. 1996 Jan;16(1):369-75
references.pmid: 8524316
references.citation: J Immunol. 2004 Apr 1;172(7):4151-8
references.pmid: 15034027
references.citation: Science. 1994 Nov 18;266(5188):1253-5
references.pmid: 7973709