title: Antibacterial cathelicidin peptide CAP11 inhibits the lipopolysaccharide (LPS)-induced suppression of neutrophil apoptosis by blocking the binding of LPS to target cells.
abstract: OBJECTIVE
  The action of antibacterial cathelicidin CAP11 (cationic antibacterial polypeptide of 11 kDa) on the lipopolysaccharide (LPS)-induced suppression of neutrophil apoptosis was evaluated in vitro.
  
  
  METHODS
  Human neutrophils (10(6) cells/ml) were incubated alone or with mononuclear cells (6 x 10(5) cells/ml) in the presence of LPS (10 ng/ml) and CAP 11 (0.1 approximately 10 microg/ml), and neutrophil apoptosis was determined.
  
  
  RESULTS
  LPS suppressed neutrophil apoptosis, accompanied with the activation of NF-kappaB, phosphorylation of extracellular signal-related protein kinase (ERK), expression of Bcl-XL (an anti-apoptotic protein) and inhibition of caspase 3 activity. Interestingly, CAP11 (> 1 microg/ml) reversed the actions of LPS to trigger these changes, and induced neutrophil apoptosis (p < 0.0001). Moreover, neutralizing antibodies against Mac-1 (CD11b/CD18) and Toll-like receptor (TLR) 4 completely blocked the LPS-induced suppression of neutrophil apoptosis (p < 0.0001), suggesting a major role of Mac-1 and TLR4 in the LPS-mediated neutrophil activation. In addition, LPS activated monocytes to produce proinflammatory cytokines (IL-1beta, TNF-alpha and IL-8) and inhibited neutrophil apoptosis. Importantly, CAP11 (> 1 microg/ml) reduced the cytokine production, thereby inducing neutrophil apoptosis (p < 0.0001). Finally, CAP11 (> 1 microg/ml) strongly suppressed the LPS-binding to neutrophils and monocytes (p < 0.01).
  
  
  CONCLUSIONS
  CAP11 is able to block the LPS-induced survival of neutrophils via the suppression of anti-apoptotic signaling in neutrophils and cytokine production from monocytes by inhibiting the binding of LPS to target cells.
authors.affiliation: Department of Host Defense and Biochemical Research, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. nagaokai@med.juntendo.ac.jp
authors.forename: I
authors.initials: I
authors.lastname: Nagaoka
authors.forename: S
authors.initials: S
authors.lastname: Yomogida
authors.forename: H
authors.initials: H
authors.lastname: Tamura
authors.forename: M
authors.initials: M
authors.lastname: Hirata
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D051020:bcl-X Protein
chemical_list: D023181:Antimicrobial Cationic Peptides; C494811:BCL2L1 protein, human; C440609:CAP11 protein, Cavia; D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3