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.
Publication types
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Clinical Trial
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimicrobial Cationic Peptides / chemical synthesis
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Antimicrobial Cationic Peptides / immunology
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Antimicrobial Cationic Peptides / pharmacology*
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Calcium / immunology
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Calcium / metabolism
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Cathelicidins
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Cell Line, Tumor
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Female
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Humans
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Immunologic Factors / chemical synthesis
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Immunologic Factors / immunology
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Immunologic Factors / pharmacology*
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Male
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / immunology
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Monocytes / cytology
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Monocytes / immunology*
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Monocytes / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-akt / metabolism
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src-Family Kinases / genetics
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src-Family Kinases / immunology*
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src-Family Kinases / metabolism
Substances
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Antimicrobial Cationic Peptides
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Immunologic Factors
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lyn protein-tyrosine kinase
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src-Family Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase Kinases
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Calcium
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Cathelicidins