Dubuquoy Laurent, Jansson Emmelie A, Deeb Samir, Rakotobe Sabine, Karoui Mehdi, Colombel Jean-Frédéric, Auwerx Johan, Pettersson Sven, Desreumaux Pierre
Equipe Propre INSERM 0114 sur la Physiopathologie des Maladies Inflammatoires Intestinales, Lille, France.
Gastroenterology. 2003 May;124(5):1265-76. doi: 10.1016/s0016-5085(03)00271-3.
BACKGROUND & AIMS: The peroxisome proliferator-activated receptor gamma (PPAR gamma) has been proposed as a key inhibitor of colitis through attenuation of nuclear factor kappa B (NF-kappa B) activity. In inflammatory bowel disease, activators of NF-kappa B, including the bacterial receptor toll-like receptor (TLR)4, are elevated. We aimed to determine the role of bacteria and their signaling effects on PPAR gamma regulation during inflammatory bowel disease (IBD).
TLR4-transfected Caco-2 cells, germ-free mice, and mice devoid of functional TLR4 (Lps(d)/Lps(d) mice) were assessed for their expression of PPAR gamma in colonic tissues in the presence or absence of bacteria. This nuclear receptor expression and the polymorphisms of gene also were assessed in patients with Crohn's disease (CD) and ulcerative colitis (UC), 2 inflammatory bowel diseases resulting from an abnormal immune response to bacterial antigens.
TLR4-transfected Caco-2 cells showed that the TLR4 signaling pathway elevated PPAR gamma expression and a PPAR gamma-dependent reporter in an I kappa kappa beta dependent fashion. Murine and human intestinal flora induced PPAR gamma expression in colonic epithelial cells of control mice. PPAR gamma expression was significantly higher in the colon of control compared with Lps(d)/Lps(d) mice. Although PPAR gamma levels appeared normal in patients with CD and controls, UC patients displayed a reduced expression of PPAR gamma confined to colonic epithelial cells, without any mutation in the PPAR gamma gene.
These data showed that the commensal intestinal flora affects the expression of PPAR gamma and that PPAR gamma expression is considerably impaired in patients with UC.
过氧化物酶体增殖物激活受体γ（PPARγ）被认为是通过减弱核因子κB（NF-κB）活性来抑制结肠炎的关键因子。在炎症性肠病中，包括细菌受体Toll样受体（TLR）4在内的NF-κB激活剂水平升高。我们旨在确定炎症性肠病（IBD）期间细菌及其信号传导对PPARγ调节的作用。
在有或无细菌存在的情况下，评估转染TLR4的Caco-2细胞、无菌小鼠和缺乏功能性TLR4的小鼠（Lps(d)/Lps(d)小鼠）结肠组织中PPARγ的表达。还评估了克罗恩病（CD）和溃疡性结肠炎（UC）患者（这两种炎症性肠病是对细菌抗原的异常免疫反应所致）的这种核受体表达及基因多态性。
转染TLR4的Caco-2细胞显示，TLR4信号通路以IκB激酶β依赖性方式提高PPARγ表达和PPARγ依赖性报告基因。小鼠和人类肠道菌群可诱导对照小鼠结肠上皮细胞中PPARγ表达。与Lps(d)/Lps(d)小鼠相比对照小鼠结肠中PPARγ表达显著更高。尽管CD患者和对照者的PPARγ水平看似正常，但UC患者局限于结肠上皮细胞的PPARγ表达降低，且PPARγ基因无任何突变。
这些数据表明共生肠道菌群影响PPARγ表达，且UC患者的PPARγ表达明显受损。
