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KGF Improves Intestinal Structure and Function in a Mouse Model of Intestinal Ischemia/Reperfusion: Mechanism Involved in the Up-regulation of Epithelial Derived IL-7Expression

Author: CaiZuoJiao
Tutor: YangZuo
School: Third Military Medical University
Course: Surgery
Keywords: Keratinocyte growth factor (KGF) Interleukin-7(IL-7) ischemia/reperfusion (I/R) mouse intestinal epithelial cells intestinal barrier function signaltransducers and activators of transcription1(STAT1) interferon regulatory factor1(IRF-1)and interferon regulatory factor2(IRF-2)
CLC: R656.7
Type: PhD thesis
Year: 2012
Downloads: 60
Quote: 0
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Background:Intestinal ischemia/reperfusion (I/R) induces the desquamation of the intestinalepithelium, increases the intestinal permeability, and in patients often causes fatal conditionsincluding sepsis and multiple organ failure. Keratinocyte growth factor (KGF) increasesintestinal growth, although little is known about the effect of KGF on intestinal function afterintestinal I/R. Epithelial cell (EC) derived Interleukin-7(IL-7) plays a crucial role in controlof neighbouring intraepithelial lymphocytes (IEL) development and homeostasis, and IELderived KGF promotes intestinal epithelial growth, which was regulated by EC-derived IL-7.These two factors are both important involved in the regulation of gastrointestinal cell growthand function. Base on this, we hypothesized that KGF administration would improve theintestinal function in a mouse model of acute intestinal I/R, we also hypothesized that there isa crosstalk between IELs and ECs through IEL derived KGF and EC derived IL-7, and KGFcould regulate the EC-derived IL-7expression. Furthermore, to investigate the mechanisminvolved in this regulation of IL-7expression by KGF.Methods:Firstly, adult C57BL/6J mice undergoing intestinal I/R injury were treated withrecombinant KGF. Mice were killed after surgery, and the small bowel was harvested forhistology, wet weight, RNA and protein content analysis. ECs proliferation was detected byimmunohistochemistry for PCNA, and apoptosis was determined by TUNEL staining. Theexpressions of Claudin-1and ZO-1were detected by immunohistochemistry. Epithelialbarrier function was assessed with transepithelial resistance (TER).Secondly, histological evaluation was performed in small intestine tissues of patients with intestinal obstruction and IL-7expression was detected by immunofluorescence.Intestinal epithelial cells (LoVo cells) and adult C57BL/6J mice were treated withrecombinant KGF. KGF, KGF receptor (KGFR) and IL-7expressions were measured withwestern blot and immunofluorescence analysis.Thirdly, LoVo cells and adult C57BL/6J mice were treated with KGF. Changes of IL-7expression following KGFR blockade or KGFR RNA interference with KGF treatment andexpression of P-Tyr-STAT1, STAT1, and IL-7by inhibiting STAT1and alterations ofexpression of IRF-1, IRF-2and IL-7following IRF-1and IRF-2RNA interference with KGFtreatment were measured with western blot. In addition, IRF-1, IRF-2expression weredetected by immunofluorescence in vitro and immunohistochemistry analysis in vivo.Results:1. KGF treatment significantly increased the intestinal mucosal wet weight, contents ofintestinal mucosal protein and RNA, villus height, crypt depth and crypt cell proliferation,while KGF administration resulted in the decrease of EC apoptosis in a mouse model ofintestinal I/R.2. KGF also stimulated the recovery of mucosal structures and attenuated the disrupteddistribution of TJ proteins in a mouse model of intestinal I/R.3. Moreover, KGF administration attenuated the intestinal I/R-induced decrease in TERand maintained the intestinal barrier function.4. KGF expression in the intestinal mucosa significantly decreased while IL-7expressionincreased early after acute intestinal I/R in a mouse model.5. KGF treatment significantly increased the EC derived IL-7expression both in vitroand in vivo studies. In addition, KGF administration significantly attenuated the decreasing ofIL-7expression caused by acute intestinal I/R.6. IL-7expression was decreased after KGFR blockade or KGFR expression wassilenced by using interfering RNA in LoVo cells, even following KGF treatment.7. KGF treatment led to increased levels of P-Tyr-STAT1, RPM and AG490bothblocked P-Tyr-STAT1and IL-7expression in LoVo cells.8. IRF-1and IRF-2expressions in vivo and in vitro studies are also up-regulated by KGF,and IL-7expression was decreased after IRF-1or IRF-2expression was silenced by usinginterfering RNA following KGF treatment, respectively. Conclusion:KGF administration improves the intestinal structure and intestinal barrier function in amouse model of intestinal I/R. KGF could up-regulate the EC derived IL-7expression both invitro and in vivo through KGFR/STAT1/IRF-1, IRF-2signaling pathway. These findings arethe first report of mechanism that KGFR/STAT1/IRF-1, IRF-2pathway involved in theregulation of IL-7expression by KGF, which suggest that KGF may play an important role inthe regulation of IEL function by regulating IL-7expression.

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