Abstract
Antimicrobial peptides (AMPs) are an ancient group of defense molecules distributed in nature being found in mammals, birds, amphibians, insects, plants, and microorganisms. They display antimicrobial as well as immunomodulatory properties. The aim of this study was to investigate, for the first time, the anti-inflammatory activities of two synthetic temporin-L analogues (here named peptide 1 and 2) by an in vivo model of inflammation caused by intraperitoneal sub-lethal dose of zymosan. Our results show that peptide 1 and 2 exert anti-inflammatory activity in vivo in response to zymosan-induce peritonitis. Simultaneous administration of 10 mg/kg of both temporins, with a sub-lethal dose of zymosan (500 mg/kg), significantly rescued mice from the classical hallmarks of inflammation, including leukocyte infiltration and synthesis of inflammatory mediators including IL-6, TNF-α and MCP-1. More importantly, flow cytometry analysis highlighted a selective modulation of infiltrating inflammatory monocytes (defined as B220−/GR1hi-F480hi/CD115+) after peptide 2 treatment. Our results and presented models offer the possibility to test, in a preclinical setting, the potential of temporin analogues as anti-inflammatory agents.
Highlights
The high interest in antimicrobial peptides (AMPs), as new therapeutic agents, is stimulated by their possible use for the treatment of several infectious diseases, due to their antimicrobial activity and to their immunomodulatory properties [1].Antimicrobial peptides (AMPs) represent an abundant group of molecules that are an intrinsic component of innate immunity in multicellular organisms and they show a potent activity against Gram-positive and -negative bacteria, fungi and viruses [2]
We reported a novel library of antimicrobial peptides correlated to [Pro3, DLeu9]TL, named peptide 1 (Fig. 1), with improved antimicrobial activity [6,7]
In light of the safety of peptide 1 and 2 evidenced through in vitro evaluations on J774 macrophages, we investigated the role of both peptides in an in vivo model of inflammation that allowed for the characterization of leukocyte recruitment and local inflammatory mediator production
Summary
AMPs represent an abundant group of molecules that are an intrinsic component of innate immunity in multicellular organisms and they show a potent activity against Gram-positive and -negative bacteria, fungi and viruses [2]. Membrane disruptive AMPs present a net positive charge, ranging from +2 to +9, crucial to create electrostatic interactions with negatively charged cellular membrane of bacteria, disturbing the membrane permeability and causing a rapid cell death. In this scenario, temporins, first isolated from the skin secretions of the red frog Rana temporaria, are the largest family of membrane disruptive AMPs [4]. The amphibian peptide temporins have generally, an amidated C-terminus, a low positive charge due to the presence of 2 or more basic residues in their whole sequence and adopt an amphipathic α-helical-like preferential conformation in a hydrophobic environment [5]
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