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Anti-Inflammatory Action of an Antimicrobial Model Peptide That Suppresses the TRIF-Dependent Signaling Pathway via Inhibition of Toll-Like Receptor 4 Endocytosis in Lipopolysaccharide-Stimulated Macrophages
- Source :
- PLoS ONE, PLOS ONE(10): 5, PLoS ONE, Vol 10, Iss 5, p e0126871 (2015)
- Publication Year :
- 2015
- Publisher :
- Public Library of Science, 2015.
-
Abstract
- Antimicrobial peptides (AMPs), also called host defense peptides, particularly those with amphipathic helical structures, are emerging as target molecules for therapeutic development due to their immunomodulatory properties. Although the antimicrobial activity of AMPs is known to be exerted primarily by permeation of the bacterial membrane, the mechanism underlying its anti-inflammatory activity remains to be elucidated. We report potent anti-inflammatory activity of WALK11.3, an antimicrobial model peptide with an amphipathic helical conformation, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. This peptide inhibited the expression of inflammatory mediators, including nitric oxide, COX-2, IL-1 beta, IL-6, INF-beta, and TNF-alpha. Although WALK11.3 did not exert a major effect on all downstream signaling in the MyD88-dependent pathway, toll-like receptor 4 (TLR4)-mediated pro-inflammatory signals were markedly attenuated in the TRIF-dependent pathway due to inhibition of the phosphorylation of STAT1 by attenuation of IRF3 phosphorylation. WALK11.3 specifically inhibited the endocytosis of TLR4, which is essential for triggering TRIF-mediated signaling in macrophage cells. Hence, we suggest that specific interference with TLR4 endocytosis could be one of the major modes of the anti-inflammatory action of AMPs. Our designed WALK11 peptides, which possess both antimicrobial and anti-inflammatory activities, may be promising molecules for the development of therapies for infectious inflammation.
- Subjects :
- Signal peptide
Lipopolysaccharides
Antimicrobial peptides
Interleukin-1beta
Drug Evaluation, Preclinical
Lipopolysaccharide Receptors
lcsh:Medicine
Biology
Endocytosis
Nitric Oxide
Cell Line
Mice
Anti-Infective Agents
Animals
lcsh:Science
Toll-like receptor
Multidisciplinary
Interleukin-6
Macrophages
lcsh:R
Anti-Inflammatory Agents, Non-Steroidal
Cell biology
Toll-Like Receptor 4
Adaptor Proteins, Vesicular Transport
Biochemistry
TRIF
Cyclooxygenase 2
TLR4
Phosphorylation
lcsh:Q
Signal transduction
Inflammation Mediators
Peptides
Research Article
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 10
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....0fdba91ed4e0a14c91c0bcc48e8ca281