Peroxisome proliferator activated receptor γ in colonic epithelial cells protects against experimental inflammatory bowel disease
Peroxisome proliferator activated receptor γ in colonic epithelial cells protects against experimental inflammatory bowel disease
复制标题
DOI：
10.1136/gut.2005.081745
复制
发表时间：
2006-08-01
期刊：
影响因子：
24.5
通讯作者：
Gonzalez, F. J.
中科院分区：
文献类型：
--
作者：
Adachi, M.;Kurotani, R.;Gonzalez, F. J.
引言：过氧化物酶体增殖物激活受体γ（PPAR γ）在上皮细胞、巨噬细胞、T和B淋巴细胞中表达。据报道，配体诱导的过氧化物酶体增殖物激活受体γ的活化可减弱结肠炎活性，但尚不清楚这种保护作用是由上皮细胞还是白细胞过氧化物酶体增殖物激活受体γ介导的。在肠上皮细胞中靶向破坏PPAR γ基因的小鼠，使用villin-Cre转基因和floxed PPAR γ等位基因产生，并命名为PPAR γ（Δ IEpC）与仅具有PPARgamma floxed等位基因而没有Cre转基因的同窝小鼠（命名为PPARgamma（F/F））进行比较，所述Cre转基因在肠道中表达PPARgamma。通过给予葡聚糖硫酸钠（DSS）诱导结肠炎，并比较两种小鼠系的典型疾病症状和炎性细胞因子的表达。结果：PPARgamma（DeltaIEpC）小鼠肠组织中PPARgamma靶基因ADRP和FABP的表达降低，但其它方面正常。与PPARgamma（F/F）小鼠相比，在PPARgamma（Delta DIEpC）小鼠中发现对DSS诱导的结肠炎的易感性增加，如通过体重减轻、结肠长度、腹泻、出血评分和组织学改变所定义的。在用DSS治疗的PPAR γ δ（DIEpC）小鼠的结肠中，白细胞介素（IL）-6、IL-1 β和肿瘤坏死因子α mRNA水平高于类似治疗的PPAR γ（F/F）小鼠。PPARgamma配体罗格列酮降低DSS诱导的结肠炎的严重程度，并抑制细胞因子的产生在两个PPARgamma（F/F）和PPARgamma Delta（DIEpC）mice.Conclusions：这些研究表明，在结肠上皮中表达的PPARgamma具有内源性的作用，在对DSS诱导的结肠炎的保护和罗格列酮可以通过PPARc独立的途径来抑制炎症。
Introduction: Peroxisome proliferator activated receptor gamma (PPAR gamma) is expressed in epithelial cells, macrophage, and T and B lymphocytes. Ligand induced activation of PPAR gamma was reported to attenuate colitis activity but it is not clear whether this protection is mediated by epithelial or leucocyte PPAR gamma.Methods: Mice with targeted disruption of the PPAR gamma gene in intestinal epithelial cells, generated using a villin-Cre transgene and floxed PPAR gamma allele and designated PPAR gamma(Delta IEpC), were compared with littermate mice having only the PPAR gamma floxed allele with no Cre transgene that expressed PPAR gamma in the gut, designated PPAR gamma(F/F). Colitis was induced by administering dextran sodium sulphate (DSS) and the two mouse lines compared for typical symptoms of disease and expression of inflammatory cytokines. \Results: PPAR gamma(Delta IEpC) mice displayed reduced expression of the PPAR gamma target genes ADRP and FABP in the gut but were otherwise normal. Increased susceptibility to DSS induced colitis, as defined by body weight loss, colon length, diarrhoea, bleeding score, and altered histology, was found in PPAR gamma(Delta DIEpC) mice in comparison with PPAR gamma(F/F) mice. Interleukin (IL)-6, IL-1 beta, and tumour necrosis factor a mRNA levels in colons of PPAR gamma Delta(DIEpC) mice treated with DSS were higher than in similarly treated PPAR gamma(F/F) mice. The PPAR gamma ligand rosiglitazone decreased the severity of DSS induced colitis and suppressed cytokine production in both PPAR gamma(F/F) and PPAR gamma Delta(DIEpC) mice.Conclusions: These studies reveal that PPAR gamma expressed in the colonic epithelium has an endogenous role in protection against DSS induced colitis and that rosiglitazone may act through a PPARc independent pathway to suppress inflammation.