rss
Gut 52:735-741 doi:10.1136/gut.52.5.735
  • Colon

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

  1. J Schauber1,
  2. C Svanholm2,*,
  3. S Termén3,*,
  4. K Iffland1,
  5. T Menzel1,
  6. W Scheppach1,
  7. R Melcher1,
  8. B Agerberth3,
  9. H Lührs1,
  10. G H Gudmundsson4
  1. 1Department of Medicine, Division of Gastroenterology, University of Würzburg, Germany
  2. 2Microbiology and Tumour Biology Centre, Karolinska Institute, Stockholm, Sweden
  3. 3Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
  4. 4Microbiology and Tumour Biology Centre, Karolinska Institute, Stockholm, Sweden, and Institute of Biology, University of Iceland, Reykjavik, Iceland
  1. Correspondence to:
    Dr J Schauber, Medizinische Klinik, Schwerpunkt Gastroenterologie, Josef-Schneider-Str 2, 97080 Würzburg, Germany;
    j.schauber{at}medizin.uni-wuerzburg.de
  • Accepted 12 November 2002

Abstract

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.

Footnotes

  • * C Svanholm and S Termén contributed equally to this work.