Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes:: relevance of signalling pathways

被引:303
作者
Schauber, J
Svanholm, C
Termén, S
Iffland, K
Menzel, T
Scheppach, W
Melcher, R
Agerberth, B
Lührs, H
Gudmundsson, GH
机构
[1] Univ Wurzburg, Dept Med, Div Gastroenterol, Med Klin, D-97080 Wurzburg, Germany
[2] Karolinska Inst, Microbiol & Tumour Biol Ctr, Stockholm, Sweden
[3] Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden
[4] Karolinska Inst, Microbiol & Tumour Biol Ctr, Stockholm, Sweden
[5] Univ Iceland, Inst Biol, Reykjavik, Iceland
关键词
D O I
10.1136/gut.52.5.735
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
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页码:735 / 741
页数:7
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