Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes:: relevance of signalling pathways
Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes:: relevance of signalling pathways
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DOI：
10.1136/gut.52.5.735
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发表时间：
2003-05-01
期刊：
影响因子：
24.5
通讯作者：
Gudmundsson, GH
中科院分区：
文献类型：
--
作者：
Schauber, J;Svanholm, C;Gudmundsson, GH
背景与目的：短链脂肪酸（SCFA）对结肠粘膜有重要影响。特别地，SCFA调节粘膜免疫功能。抗微生物凯萨林菌素LL-37由结肠上皮细胞表达。方法：采用免疫组化法检测LL-37在体内的表达。采用真实的时间定量逆转录-聚合酶链反应来测定用各种细胞因子、SCFA或黄酮处理后体外结肠细胞中LL-37的表达。LL-37水平与通过碱性磷酸酶（AP）活性确定的细胞分化相关。此外，还对细胞内信号转导通路如MEK-ERK（mitogen/extracellular signal protein kinase，MEK）/extracellular signal regulated protein kinase，ERK）和p38/mitogen activated protein kinase（MAP）进行了研究。在结肠细胞中，在丁酸盐、异丁酸盐、丙酸盐和阿司他丁A处理后，在体外检测到与细胞分化相关的LL-37表达增加。黄酮诱导LL-37转录，但不影响AP活性，而细胞因子没有影响。为了剖析介导分化和LL-37表达的途径，应用了特异性抑制剂。蛋白激酶MEK的抑制增强丁酸诱导的AP活性，而LL-37在结肠上皮细胞中的表达被阻断。相反，抑制p38/MAP激酶阻断细胞分化，而不抑制LL-37 expression.Conclusions：表达的cathelicidin LL-37在结肠细胞和细胞分化分别调制SCFA通过不同的信号通路。这些数据可能提供了一个合理的饮食调节粘膜防御机制。
Background and aims: Short chain fatty acids (SCFA) exert profound effects on the colonic mucosa. In particular, SCFA modulate mucosal immune functions. The antimicrobial cathelicidin LL-37 is expressed by colon epithelial cells. In the present study the effect of SCFA on LL-37 expression was investigated.Methods: LL-37 expression in vivo was assessed by immunohistochemistry. Real time quantitative reverse transcription-polymerase chain reaction was employed to determine LL-37 expression in colonocytes in vitro after treatment with various cytokines, SCFA, or flavone. LL-37 levels were correlated to cell differentiation which was determined by alkaline phosphatase (AP) activity. In addition, intracellular signalling pathways such as MEK-ERK (mitogen/extracellular signal protein kinase (MEK)/extracellular signal regulated protein kinase (ERK)) and p38/mitogen activated protein ( MAP) kinase were explored.Results: In vivo, LL-37 expression in healthy mucosa was restricted to differentiated epithelial cells in human colon and ileum. In colonocytes, increased LL-37 expression associated with cell differentiation was detected in vitro following treatment with butyrate, isobutyrate, propionate, and trichostatin A. Flavone induced LL-37 transcription but did not affect AP activity while cytokines had no effect. To dissect pathways mediating differentiation and LL-37 expression, specific inhibitors were applied. Inhibition of the protein kinase MEK enhanced butyrate induced AP activity while LL-37 expression in colon epithelial cells was blocked. In contrast, inhibition of p38/MAP kinase blocked cell differentiation without inhibiting LL-37 expression.Conclusions: Expression of the cathelicidin LL-37 in colonocytes and cellular differentiation are separately modulated by SCFA via distinct signalling pathways. These data may provide a rationale for dietary modulation of mucosal defence mechanisms.