Antimicrobial peptides and endotoxin inhibit cytokine and nitric oxide release but amplify respiratory burst response in human and murine macrophages

• Type of Material: Article
• Authors: Susu M Zughaier, Emory University; William M Shafer, Emory University; David S Stephens, Emory University
• Language: English
• Date: 2005-09
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2005 Blackwell Publishing Ltd
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1111/j.1462-5822.2005.00549.x/abstract
• Title of Journal or Parent Work: Cellular Microbiology
• ISSN: 1462-5814
• Volume: 7
• Issue: 9
• Start Page: 1251
• End Page: 1262
• Grant/Funding Information: This work was supported by NIH Grants R01 AI033517 to D.S.S and AI 043316 to W.M.S. W.M.S is the recipient of a Senior Research Career Scientist Award from VA Medical Research Service.; National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
• Research Categories: Health Sciences, Immunology; Biology, Microbiology

Abstract

Antimicrobial peptides (AMPs), in addition to their antibacterial properties, are also chemotactic and signalling molecules that connect the innate and adaptive immune responses. The role of AMP [α defensins, LL-37, a cathepsin G-derived peptide (CG117-136), protegrins (PG-1), polymyxin B (PMX) and LLP1] in modulating the respiratory burst response in human and murine macrophages in the presence of bacterial endotoxin [lipopolysaccharide (LPS) or lipooligosaccharide (LOS)] was investigated. AMP were found to neutralize endotoxin induction of nitric oxide and TNFα release in macrophages in a dose-dependent manner. In contrast, macrophages primed overnight with AMP and LOS or LPS significantly enhanced reactive oxygen species (ROS) release compared with cells primed with endotoxin or AMP alone, while no responses were seen in unprimed cells. This enhanced ROS release by macrophages was seen in all cell lines including those obtained from C3H/HeJ (TLR4−/−) mice. Similar effects were also seen when AMP and endotoxin were added directly with zymosan to trigger phagocytosis and the respiratory burst in unprimed RAW 264.7 and C3H/HeJ macrophages. Amplification of ROS release was also demonstrated in a cell-free system of xanthine and xanthine oxidase. Although AMP inhibited cytokine and nitric oxide induction by endotoxin in a TLR4-dependent manner, AMP and endotoxin amplified ROS release in a TLR4-independent manner possibly by exerting a prolonged catalytic effect on the ROS generating enzymes such as the NADPH-oxidase complex.