Role of nuclear hormone receptors in butyrate-mediated up-regulation of the antimicrobial peptide cathelicidin in epithelial colorectal cells.
OBJECTIVE
The human cathelicidin (LL-37) is one of the major antimicrobial peptides of the non-specific innate immune system in the intestinal tract. Altered expression has been associated with gastrointestinal disease. Recent studies demonstrated that butyrate induces LL-37 mRNA in colonic epithelial cells, however the underlying molecular mechanisms have not been elucidated. The objective of this study was to investigate the regulatory pathways involved in butyrate-induced up-regulation of LL-37.


RESULTS
Treatment of Caco-2 and HT-29 cells with butyrate led to a time-dependent up-regulation of LL-37 mRNA expression as determined by semi-quantitative RT-PCR. Up-regulation of LL-37 mRNA by butyrate was subsequently followed by an increase in LL-37 protein expression as observed by immunofluorescence. Co-incubation of butyrate with a VDR, p38 MAPK, ERK 1/2 and TGF-beta1 receptor kinase inhibitor all reduced butyrate-mediated LL-37 mRNA up-regulation. In contrast, transfection of Caco-2 cells with a dominant-negative PPARgamma mutant vector did not affect butyrate-mediated up-regulation of LL-37 mRNA.


CONCLUSIONS
Our results clearly demonstrate that butyrate-mediated up-regulation of LL-37 is influenced by several signalling pathways and receptors including MAPKs as well as VDR and TGF-beta1, but not by PPARgamma. These data may provide new opportunities in the treatment of gastrointestinal diseases.
Schwab
Markus
M
First Department of Medicine, ZAFES, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Reynders
Veerle
V
Shastri
Yogesh
Y
Loitsch
Stefan
S
Stein
Jürgen
J
Schröder
Oliver
O
D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use; D018938:Caco-2 Cells; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D002087:Butyrates; D047428:Protein Kinase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D054804:Cathelicidins