Article: article from journal or magazin.
Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-alpha by blocking the binding of LPS to CD14(+) cells.
Journal of Immunology
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Mammalian myeloid and epithelial cells express several kinds of antibacterial peptides (alpha-/beta-defensins and cathelicidins) that contribute to the innate host defense by killing invading micro-organisms. In this study we evaluated the LPS-neutralizing activities of cathelicidin peptides human CAP18 (cationic antibacterial proteins of 18 kDa) and guinea pig CAP11 using the CD14(+) murine macrophage cell line RAW264.7 and the murine endotoxin shock model. Flow cytometric analysis revealed that CAP18 and CAP11 inhibited the binding of FITC-conjugated LPS to RAW264.7 cells. Likewise, Northern and Western blot analyses indicated that CAP18 and CAP11 suppressed LPS-induced TNF-alpha mRNA and protein expression by RAW264.7 cells. Interestingly, CAP18 and CAP11 possessed LPS-binding activities, and they strongly suppressed the interaction of LPS with LPS binding protein that mediates the transport of LPS to CD14 to facilitate the activation of CD14(+) cells by LPS. Moreover, when CAP18 and CAP11 were preincubated with RAW264.7 cells, they bound to the cell surface CD14 and inhibited the binding of FITC-LPS to the cells. Furthermore, in the murine endotoxin shock model, CAP18 or CAP11 administration inhibited the binding of LPS to CD14(+) cells (peritoneal macrophages) and suppressed LPS-induced TNF-alpha expression by these cells. Together these observations indicate that cathelicidin peptides CAP18 and CAP11 probably exert protective actions against endotoxin shock by blocking the binding of LPS to CD14(+) cells, thereby suppressing the production of cytokines by these cells via their potent binding activities for LPS and CD14.
Acute-Phase Proteins, Amino Acid Sequence, Animals, Anti-Bacterial Agents/pharmacology, Anti-Bacterial Agents/therapeutic use, Antigens, CD14/metabolism, Antimicrobial Cationic Peptides/pharmacology, Antimicrobial Cationic Peptides/therapeutic use, Carrier Proteins/metabolism, Cathelicidins, Cell Line, Depression, Chemical, Drug Evaluation, Preclinical, Gene Expression Regulation/drug effects, Guinea Pigs, Humans, Lipopolysaccharides/antagonists & inhibitors, Lipopolysaccharides/metabolism, Macrophages/drug effects, Macrophages/metabolism, Macrophages, Peritoneal/drug effects, Macrophages, Peritoneal/metabolism, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Prodrugs/pharmacology, Prodrugs/therapeutic use, Protein Binding/drug effects, RNA, Messenger/biosynthesis, Shock, Septic/prevention & control, Tumor Necrosis Factor-alpha/biosynthesis, Tumor Necrosis Factor-alpha/genetics
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