title: The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice.
abstract: BACKGROUND
  Clostridium difficile mediates intestinal inflammation by releasing toxin A (TxA), a potent enterotoxin. Cathelicidins (Camp as gene name, LL-37 peptide in humans and mCRAMP peptide in mice) are antibacterial peptides that also posses anti-inflammatory properties.
  
  
  OBJECTIVE
  To determine the role of cathelicidins in models of Clostridium difficile infection and TxA-mediated ileal inflammation and cultured human primary monocytes.
  
  
  METHODS
  Wild-type (WT) and mCRAMP-deficient (Camp(-/-)) mice were treated with an antibiotic mixture and infected orally with C difficile. Some mice were intracolonically given mCRAMP daily for 3 days. Ileal loops were also prepared in WT mice and treated with either saline or TxA and incubated for 4 h, while some TxA-treated loops were injected with mCRAMP.
  
  
  RESULTS
  Intracolonic mCRAMP administration to C difficile-infected WT mice showed significantly reduced colonic histology damage, apoptosis, tissue myeloperoxidase (MPO) and tumour necrosis factor (TNF)α levels. Ileal mCRAMP treatment also significantly reduced histology damage, tissue apoptosis, MPO and TNFα levels in TxA-exposed ileal loops. WT and Camp(-/-) mice exhibited similar intestinal responses in both models, implying that C difficile/TxA-induced endogenous cathelicidin may be insufficient to modulate C difficile/TxA-mediated intestinal inflammation. Both LL-37 and mCRAMP also significantly reduced TxA-induced TNFα secretion via inhibition of NF-κB phosphorylation. Endogenous cathelicidin failed to control C difficile and/or toxin A-mediated inflammation and even intestinal cathelicidin expression was increased in humans and mice.
  
  
  CONCLUSIONS
  Exogenous cathelicidin modulates C difficile colitis by inhibiting TxA-associated intestinal inflammation. Cathelicidin administration may be a new anti-inflammatory treatment for C difficile toxin-associated disease.
authors: Inflammatory Bowel Disease Center, Division of Digestive Diseases, the University of California Los Angeles, Los Angeles, California, USA.
authors: Tressia C
authors: TC
authors: Hing
authors: Samantha
authors: S
authors: Ho
authors: David Q
authors: DQ
authors: Shih
authors: Ryan
authors: R
authors: Ichikawa
authors: Michelle
authors: M
authors: Cheng
authors: Jeremy
authors: J
authors: Chen
authors: Xinhua
authors: X
authors: Chen
authors: Ivy
authors: I
authors: Law
authors: Robert
authors: R
authors: Najarian
authors: Ciaran P
authors: CP
authors: Kelly
authors: Richard L
authors: RL
authors: Gallo
authors: Stephan R
authors: SR
authors: Targan
authors: Charalabos
authors: C
authors: Pothoulakis
authors: Hon Wai
authors: HW
authors: Koon
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D054804:Cathelicidins / Q000378:metabolism / Q000494:pharmacology; D016360:Clostridioides difficile / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D004768:Enterotoxins / Q000037:antagonists & inhibitors; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D054804:Cathelicidins; D004768:Enterotoxins; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha