title: The role of the Src family kinase Lyn in the immunomodulatory activities of cathelicidin peptide LL-37 on monocytic cells.
abstract: Cathelicidin LL-37 is a multifunctional, immunomodulatory and antimicrobial host-defense peptide of the human immune system. Here, we identified the role of SFKs in mediating the chemokine induction activity of LL-37 in monocytic cells. LL-37 induced SFK phosphorylation; and chemical inhibitors of SFKs suppressed chemokine production in response to LL-37 stimulation. SFKs were required for the downstream activation of AKT, but Ca(2+)-flux and MAPK induction were SFK-independent. Through systematic siRNA knockdown of SFK members, a requirement for Lyn in mediating LL-37 activity was identified. The involvement of Lyn in cathelicidin activities was further confirmed using Lyn-knockout mouse BMDMs. The role of SFKs and Lyn was also demonstrated in the activities of the synthetic cationic IDR peptides, developed as novel, immunomodulatory therapeutics. These findings elucidate the common molecular mechanisms mediating the chemokine induction activity of natural and synthetic cationic peptides in monocytic cells and identify SFKs as a potential target for modulating peptide responses.
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nijnik
authors.forename: Jelena
authors.initials: J
authors.lastname: Pistolic
authors.forename: Patricia
authors.initials: P
authors.lastname: Cho
authors.forename: Niall C J
authors.initials: NC
authors.lastname: Filewod
authors.forename: Reza
authors.initials: R
authors.lastname: Falsafi
authors.forename: Alexander
authors.initials: A
authors.lastname: Ramin
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Harder
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology*; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D007155:Immunologic Factors; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium; D054804:Cathelicidins