title: Immunomodulatory and Anti-Inflammatory Activities of Chicken Cathelicidin-2 Derived Peptides.
abstract: Host Defence Peptides and derived peptides are promising classes of antimicrobial and immunomodulatory lead compounds. For this purpose we examined whether chicken cathelicidin-2 (CATH-2)-derived peptides modulate the function and inflammatory response of avian immune cells. Using a chicken macrophage cell line (HD11) we found that full-length CATH-2 dose-dependently induced transcription of chemokines CXCLi2/IL-8, MCP-3 and CCLi4/RANTES, but not of pro-inflammatory cytokine IL-1β. In addition, CATH-2 efficiently inhibited IL-1β and nitric oxide production by HD11 cells induced by different sources of lipopolysaccharides (LPS). N-terminal truncated CATH-2 derived peptides maintained the capacity to selectively induce chemokine transcription, but despite their high LPS affinity several analogs lacked LPS-neutralizing capacity. Substitution of phenylalanine residues by tryptophan introduced endotoxin neutralization capacity in inactive truncated CATH-2 derived peptides. In contrast, amino acid substitution of phenylalanine by tyrosine abrogated endotoxin neutralization activity of CATH-2 analogs. These findings support a pivotal role for aromatic residues in peptide-mediated endotoxin neutralization by CATH-2 analogs and were shown to be independent of LPS affinity. The capacity to modulate chemokine production and dampen endotoxin-induced pro-inflammatory responses in chicken immune cells implicates that small CATH-2 based peptides could serve as leads for the design of CATH-2 based immunomodulatory anti-infectives.
authors: Division of Molecular Host Defence, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors: Albert
authors: A
authors: van Dijk
authors: Division of Molecular Host Defence, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors: Mandy
authors: M
authors: van Eldik
authors: Division of Molecular Host Defence, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors: Edwin J A
authors: EJ
authors: Veldhuizen
authors: Division of Molecular Host Defence, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors: Hanne L M
authors: HL
authors: Tjeerdsma-van Bokhoven
authors: Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, United States of America.
authors: Marcel R
authors: MR
authors: de Zoete
authors: Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.
authors: Floris J
authors: FJ
authors: Bikker
authors: Division of Molecular Host Defence, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors: Henk P
authors: HP
authors: Haagsman
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000235:genetics; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D002645:Chickens; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009154:Mutation; D009569:Nitric Oxide / Q000096:biosynthesis; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D023181:Antimicrobial Cationic Peptides; C504855:CMAP27 protein, chicken; D018925:Chemokines; D016207:Cytokines; D007155:Immunologic Factors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase