A highly efficient hybrid peptide ameliorates intestinal inflammation and mucosal barrier damage by neutralizing lipopolysaccharides and antagonizing the lipopolysaccharide-receptor interaction.
Animals
Anti-Inflammatory Agents
/ pharmacology
Antimicrobial Cationic Peptides
/ pharmacology
Cell Line
Inflammation
/ chemically induced
Interleukin-6
/ metabolism
Intestinal Mucosa
/ drug effects
Lipopolysaccharides
/ pharmacology
Male
Mice
Mice, Inbred C57BL
Mucous Membrane
/ drug effects
NF-kappa B
/ metabolism
Peptides
/ pharmacology
RAW 264.7 Cells
Signal Transduction
/ drug effects
Toll-Like Receptor 4
/ metabolism
Tumor Necrosis Factor-alpha
/ metabolism
NF-κB signaling
Toll-like receptor
in silico
peptide drug
proinflammatory cytokine
tight junction
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
26
12
2019
revised:
25
09
2020
accepted:
28
09
2020
pubmed:
16
10
2020
medline:
24
4
2021
entrez:
15
10
2020
Statut:
ppublish
Résumé
Intestinal inflammatory disorders, such as inflammatory bowel disease, are major contributors to mortality and morbidity in humans and animals worldwide. While some native peptides have great potential as therapeutic agents against intestinal inflammation, potential cytotoxicity, anti-inciting action, and suppression of anti-inflammatory activity may limit their development as anti-inflammatory agents. Peptide hybridization is an effective approach for the design and engineering of novel functional peptides because hybrid peptides combine the advantages and benefits of various native peptides. In the present study, a novel hybrid anti-inflammatory peptide that combines the active center of Cecropin A (C) and the core functional region of LL-37 (L) was designed [C-L peptide; C (1-8)-L (17-30)] through in silico analysis to reduce cytotoxicity and improve the anti-inflammatory activity of the parental peptides. The resulting C-L peptide exhibited lower cytotoxicity than either C or L peptides alone. C-L also exerted a protective effect against lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophages and in the intestines of a mouse model. The hybrid peptide exhibited increased anti-inflammatory activity compared to the parental peptides. C-L plays a role in protecting intestinal tissue from damage, LPS-induced weight loss, and leukocyte infiltration. In addition, C-L reduces the expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and interferon-gamma (IFN-γ), as well as reduces cell apoptosis. It also reduced mucosal barrier damage caused by LPS. The anti-inflammatory effects of the hybrid peptide were mainly attributed to its LPS-neutralizing activity and antagonizing the activation of LPS-induced Toll-like receptor 4-myeloid differentiation factor 2 (TLR4/MD2). The peptide also affected the TLR4-(nuclear factor κB) signaling pathway, modulating the inflammatory response upon LPS stimulation. Collectively, these findings suggest that the newly designed peptide, C-L, could be developed into a novel anti-inflammatory agent for animals or humans.
Identifiants
pubmed: 33058296
doi: 10.1096/fj.201903263RRR
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Antimicrobial Cationic Peptides
0
Interleukin-6
0
Lipopolysaccharides
0
NF-kappa B
0
Peptides
0
Toll-Like Receptor 4
0
Tumor Necrosis Factor-alpha
0
polypeptide C
0
cecropin A
80451-04-3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
16049-16072Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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