title: Cathelicidin signaling via the Toll-like receptor protects against colitis in mice.
abstract: OBJECTIVE
  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.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095, USA. hkoon@mednet.ucla.edu
authors.forename: Hon Wai
authors.initials: HW
authors.lastname: Koon
authors.forename: David Q
authors.initials: DQ
authors.lastname: Shih
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chen
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Bakirtzi
authors.forename: Tressia C
authors.initials: TC
authors.lastname: Hing
authors.forename: Ivy
authors.initials: I
authors.lastname: Law
authors.forename: Samantha
authors.initials: S
authors.lastname: Ho
authors.forename: Ryan
authors.initials: R
authors.lastname: Ichikawa
authors.forename: Dezheng
authors.initials: D
authors.lastname: Zhao
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.forename: Richard
authors.initials: R
authors.lastname: Gallo
authors.forename: Paul
authors.initials: P
authors.lastname: Dempsey
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D016264:Dextran Sulfate; D054804:Cathelicidins