Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón-Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain.
Inflamm Bowel Dis. 2021 Oct 18;27(10):1661-1673. doi: 10.1093/ibd/izab034.
Liver X receptor (LXR) exerts anti-inflammatory effects in macrophages. The aim of this study was to explore the expression and function of LXR in the colonic epithelium under inflammatory conditions.
The expression of LXR was explored by Western blot and immunohistochemistry in colonic biopsies from patients diagnosed with inflammatory bowel disease (IBD) and control patients. In addition, LXR and its target gene expression were analyzed in the colon from interleukin (IL)-10-deficient (IL-10-/-) and wild-type mice. Caco-2 cells were pretreated with the synthetic LXR agonist GW3965 and further challenged with IL-1β, the expression of IL-8 and chemokine (C-C motif) ligand (CCL)-28 chemokines, the activation of mitogen-activated protein (MAP) kinases, and the nuclear translocation of the p65 subunit of nuclear factor kappa B was evaluated. Glibenclamide was used as an ABCA1 antagonist.
We found that LXR expression was downregulated in colonic samples from patients with IBD and IL-10-/- mice. The nuclear positivity of LXR inversely correlated with ulcerative colitis histologic activity. Colonic IL-1β mRNA levels negatively correlated with both LXRα and LXRβ in the colon of IL-10-/- mice, where a decreased mRNA expression of the LXR target genes ABCA1 and FAS was shown. In addition, IL-1β decreased the expression of the LXR target gene ABCA1 in cultured intestinal epithelial cells. The synthetic LXR agonist GW3965 led to a decreased nuclear positivity of the p65 subunit of nuclear factor kappa B, a phosphorylation ratio of the p44-42 MAP kinase, and the expression of CCL-28 and IL-8 in IL-1β-stimulated Caco-2 cells. The pharmacological inhibition of ABCA1 increased the phosphorylation of p44-42 after GW3965 treatment and IL-1β stimulation.
The LXR-ABCA1 pathway exerts anti-inflammatory effects in intestinal epithelial cells and is impaired in the colonic mucosa of patients with IBD and IL-10-/- mice.
肝 X 受体 (LXR) 在巨噬细胞中发挥抗炎作用。本研究旨在探讨炎症状态下结肠上皮细胞中 LXR 的表达和功能。
通过 Western blot 和免疫组织化学方法检测在炎症性肠病（IBD）患者和对照患者的结肠活检组织中 LXR 的表达。此外，分析白细胞介素（IL）-10 缺陷（IL-10-/-）和野生型小鼠结肠中 LXR 及其靶基因的表达。用合成 LXR 激动剂 GW3965 预处理 Caco-2 细胞，然后用 IL-1β进一步刺激，评估 IL-8 和趋化因子（C-C 基序）配体（CCL）-28 趋化因子的表达、丝裂原激活蛋白激酶的激活以及核因子 kappa B 的 p65 亚基的核易位。使用格列本脲作为 ABCA1 拮抗剂。
我们发现 IBD 患者和 IL-10-/- 小鼠的结肠样本中 LXR 表达下调。LXR 的核阳性与溃疡性结肠炎的组织学活动呈负相关。IL-10-/- 小鼠结肠中 IL-1βmRNA 水平与 LXRα和 LXRβ均呈负相关，显示 LXR 靶基因 ABCA1 和 FAS 的 mRNA 表达降低。此外，IL-1β降低了培养的肠上皮细胞中 LXR 靶基因 ABCA1 的表达。合成的 LXR 激动剂 GW3965 导致核因子 kappa B 的 p65 亚基的核阳性降低，p44-42 MAP 激酶的磷酸化比率以及 IL-1β刺激的 Caco-2 细胞中 CCL-28 和 IL-8 的表达降低。ABCA1 的药理抑制作用增加了 GW3965 处理和 IL-1β刺激后 p44-42 的磷酸化。
LXR-ABCA1 途径在肠上皮细胞中发挥抗炎作用，在 IBD 患者和 IL-10-/- 小鼠的结肠黏膜中受损。
