Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
PLoS One. 2013 Aug 23;8(8):e73409. doi: 10.1371/journal.pone.0073409. eCollection 2013.
Helicobacter pylori is a major pathogen associated with the development of gastroduodenal diseases. It has been reported that H. pylori induced pro-inflammatory cytokine IL1B is one of the various modulators of acid secretion in the gut. Earlier we reported that IL1B-activated NFkB down-regulates gastrin, the major hormonal regulator of acid secretion. In this study, the probable pathway by which IL1B induces NFkB and affects gastrin expression has been elucidated. IL1B-treated AGS cells showed nine-fold activation of MyD88 followed by phosphorylation of TAK1 within 15 min of IL1B treatment. Furthermore, it was observed that activated TAK1 significantly up-regulates the NFkB subunits p50 and p65. Ectopic expression of NFkB p65 in AGS cells resulted in about nine-fold transcriptional repression of gastrin both in the presence and absence of IL1B. The S536A mutant of NFkB p65 is significantly less effective in repressing gastrin. These observations show that a functional NFkB p65 is important for IL1B-mediated repression of gastrin. ChIP assays revealed the presence of HDAC1 and NFkB p65 along with NCoR on the gastrin promoter. Thus, the study provides mechanistic insight into the IL1B-mediated gastrin repression via NFkB.
幽门螺杆菌是一种与胃肠道疾病发展相关的主要病原体。据报道，幽门螺杆菌诱导的促炎细胞因子白细胞介素 1B 是肠道中各种胃酸分泌调节剂之一。我们之前曾报道过，白细胞介素 1B 激活的 NFkB 下调胃泌素，这是胃酸分泌的主要激素调节剂。在这项研究中，阐明了白细胞介素 1B 诱导 NFkB 并影响胃泌素表达的可能途径。用白细胞介素 1B 处理的 AGS 细胞在白细胞介素 1B 处理后 15 分钟内显示 MyD88 激活九倍，随后 TAK1 磷酸化。此外，观察到激活的 TAK1 显著上调 NFkB 亚基 p50 和 p65。AGS 细胞中 NFkB p65 的异位表达导致胃泌素的转录抑制约九倍，无论是在存在还是不存在白细胞介素 1B 的情况下。NFkB p65 的 S536A 突变体在抑制胃泌素方面的效果明显较差。这些观察结果表明，功能性 NFkB p65 对于白细胞介素 1B 介导的胃泌素抑制很重要。ChIP 分析显示，胃泌素启动子上存在 HDAC1 和 NFkB p65 以及 NCoR。因此，该研究提供了白细胞介素 1B 介导的胃泌素抑制通过 NFkB 的机制见解。
