Cathelicidin signaling via the Toll-like receptor protects against colitis in mice.

Abstract

BACKGROUND & AIMS:

Cathelicidin (encoded by Camp) is an antimicrobial peptide in the innate immune system. We examined whether macrophages express cathelicidin in colons of mice with experimental colitis and patients with inflammatory bowel disease, and we investigated its signaling mechanisms.

METHODS:

Quantitative, real-time, reverse-transcription polymerase chain reaction (PCR), bacterial 16S PCR, immunofluorescence, and small interfering RNA (siRNA) analyses were performed. Colitis was induced in mice using dextran sulfate sodium (DSS); levels of cathelicidin were measured in human primary monocytes.

RESULTS:

Expression of cathelicidin increased in the inflamed colonic mucosa of mice with DSS-induced colitis compared with controls. Cathelicidin expression localized to mucosal macrophages in inflamed colon tissues of patients and mice. Exposure of human primary monocytes to Escherichia coli DNA induced expression of Camp messenger RNA, which required signaling by extracellular signal-regulated kinase (ERK); expression was reduced by siRNAs against Toll-like receptor (TLR)9 and MyD88. Intracolonic administration of bacterial DNA to wild-type mice induced expression of cathelicidin in colons of control mice and mice with DSS-induced colitis. Colon expression of cathelicidin was significantly reduced in TLR9(-/-) mice with DSS-induced colitis. Compared with wild-type mice, Camp(-/-) mice developed a more severe form of DSS-induced colitis, particularly after intracolonic administration of E coli DNA. Expression of cathelicidin from bone marrow-derived immune cells regulated DSS induction of colitis in transplantation studies in mice.

CONCLUSIONS:

Cathelicidin protects against induction of colitis in mice. Increased expression of cathelicidin in monocytes and experimental models of colitis involves activation of TLR9-ERK signaling by bacterial DNA. This pathway might be involved in the pathogenesis of ulcerative colitis.

• Authors: Hon Wai Koon, David Q Shih, Jeremy Chen, Kyriaki Bakirtzi, Tressia C Hing, Ivy Law, Samantha Ho, Ryan Ichikawa, Dezheng Zhao, Hua Xu, Richard Gallo, Paul Dempsey, Genhong Cheng, Stephan R Targan, Charalabos Pothoulakis
• Journal: Gastroenterology (Gastroenterology) Vol. 141 Issue 5 Pg. 1852-63.e1-3 (Nov 2011) ISSN: 1528-0012 [Electronic] United States
• PMID: 21762664 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antimicrobial Cationic Peptides
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Tlr9 protein, mouse
• Toll-Like Receptor 9
• Dextran Sulfate
• Cathelicidins

Topics

• Animals
• Antimicrobial Cationic Peptides (metabolism)
• Cells, Cultured
• Colitis (chemically induced, metabolism, prevention & control)
• Colon (metabolism, pathology)
• Dextran Sulfate (adverse effects)
• Disease Models, Animal
• Humans
• MAP Kinase Signaling System (physiology)
• Macrophages (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (metabolism, pathology)
• Myeloid Differentiation Factor 88 (metabolism)
• Signal Transduction (physiology)
• Toll-Like Receptor 9 (genetics, metabolism)
• Up-Regulation
• Cathelicidins