Article

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

Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095, USA.
Gastroenterology (impact factor: 11.68). 07/2011; 141(5):1852-63.e1-3. DOI:10.1053/j.gastro.2011.06.079
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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Keywords

bacterial 16S PCR
 
bacterial DNA
 
Cathelicidin expression localized
 
Colon expression
 
control mice
 
dextran sulfate sodium
 
DSS-induced colitis
 
E coli DNA
 
Escherichia coli DNA induced expression
 
experimental colitis
 
Increased expression
 
inflamed colonic mucosa
 
Intracolonic administration
 
mucosal macrophages
 
reverse-transcription polymerase chain reaction
 
severe form
 
TLR9-ERK signaling
 
ulcerative colitis
 
wild-type mice
 
wild-type mice induced expression