Antimicrobial host defence peptides: functions and clinical potential

Cationic host defence peptides (CHDP), also known as antimicrobial peptides, are naturally occurring peptides that can combat infections through their direct microbicidal properties and/or by influencing the host's immune responses. The unique ability of CHDP to control infections as well as resolve harmful inflammation has generated interest in harnessing the properties of these peptides to develop new therapies for infectious diseases, chronic inflammatory disorders and wound healing. Various strategies have been used to design synthetic optimized peptides, with negligible toxicity. Here, we focus on the progress made in understanding the scope of functions of CHDP and the emerging potential clinical applications of CHDP-based therapies

Functions of Cationic Host Defense Peptides in Immunity

Cationic host defense peptides are a widely distributed family of immunomodulatory molecules with antimicrobial properties. The biological functions of these peptides include the ability to influence innate and adaptive immunity for efficient resolution of infections and simultaneous modulation of inflammatory responses. This unique dual bioactivity of controlling infections and inflammation has gained substantial attention in the last three decades and consequent interest in the development of these peptide mimics as immunomodulatory therapeutic candidates. In this review, we summarize the current literature on the wide range of functions of cationic host defense peptides in the context of the mammalian immune system

Ultrashort Cationic Lipopeptides and Lipopeptoids Selectively Induce Cytokine Production in Macrophages

<div><p>A series of ultrashort lipopeptides and lipopeptoids were tested for their ability to induce cytokine production in macrophages. Fourteen compounds were found to strongly induce production of chemokines Groα and IL-8, with a structural bias that was absent from previous antibacterial activity investigations. Compounds based on LysGlyLys and <em>N</em>LysGly<em>N</em>Lys sequences did not induce cytokine production, whereas those based on LysLysLys and <em>N</em>Lys<em>N</em>Lys<em>N</em>Lys were active only when linked to a lipid tail at least sixteen carbons long. Three lipopeptides induced high levels of IL-8 production, above that of equivalent concentrations of cathelicidin LL-37, while no compound induced production of the pro-inflammatory cytokine TNF-α at or below 100 µM. Two compounds, peptoids C16OH-<em>N</em>Lys<em>N</em>Lys<em>N</em>Lys and C16OH-<em>N</em>Har<em>N</em>Har<em>N</em>Har, were selective for IL-8 production and did not induce TNF-α or IL-1β. These compounds may prove beneficial for in vivo treatment of infectious disease, with improved bioavailability over LL-37 due to their protease-resistant scaffold.</p> </div

A bioavailable form of curcumin suppresses cationic host defence peptides cathelicidin and calprotectin in a murine model of collagen-induced arthritis

Abstract Curcumin, a component of the South-Asian spice turmeric, elicits anti-inflammatory functions. We have previously demonstrated that a highly bioavailable formulation of cucurmin, Cureit/Acumin™ (CUR), can suppress disease onset and severity, in a collagen-induced arthritis (CIA) mouse model. In a previous study, we have also shown that the abundance of antimicrobial host defence peptides, specifically cathelicidin (CRAMP) and calprotectin (S100A8 and S100A9), is significantly increased in the joint tissues of CIA mice. Elevated levels of cathelicidin and calprotectin have been associated with the pathogenesis of rheumatoid arthritis. Therefore, in this study, we examined the effect CUR administration on the abundance of cathelicidin and calprotectin in the joints, in a CIA mouse model. Here, we demonstrate that daily oral administration of CUR significantly reduces the elevated levels of CRAMP and calprotectin to baseline in the joints of CIA mice. We also show a linear correlation between the abundance of these peptides in the joints with serum inflammatory cytokines TNFα, IFNγ, and MCP-1. Overall, our results suggest that oral administration of a bioavailable CUR can suppress cathelicidin and calprotectin in the joints and regulate both local (joints) and systemic (serum) inflammation, in inflammatory arthritis

Cytokine production and LDH release by human macrophage-like THP-1 cells following incubation with amphiphiles 1–21.

<p>A) IL-8 production. TC supernatants were monitored for IL-8 production by ELISA, and results were recorded in pg/mL. B) Groα production, in pg/mL. Inset: Expanded values for amphiphiles 5–7 and 21 at 5 µM and 10 µM. C) Cytotoxicity following incubation with amphiphiles 1–21. TC supernatants were monitored for LDH release as a measure of cellular toxicity, and results shown represent percent cytotoxicity over un-stimulated cells. All studies were performed in two independent biological replicates with two technical replicate each, with the data here presented as the mean plus standard error of the mean (sem) and with LL-37 data included as a positive control.</p

Structures for the cationic amphiphiles used in this study.

<p>Har = homoarginine; <i>N</i>Lys = lysine peptoid; <i>N</i>Har = homoarginine peptoid.</p

Cytokines IL-17, TNF and IFN-γ Alter the Expression of Antimicrobial Peptides and Proteins Disparately: A Targeted Proteomics Analysis using SOMAscan Technology

Antimicrobial peptides, also known as host defence peptides, are immunomodulatory molecules required to resolve infections. Antimicrobial peptides and proteins (APPs) are important in the control of infections in the lungs. Despite evidence that APPs exhibit a wide range of immune functions and modulate inflammation, the effect of inflammatory cytokines on the expression of APPs is not completely defined. In this study, we profiled the expression of 39 different APPs in human bronchial epithelial cells (HBEC) using Slow Off-rate Modified Aptamer (SOMAmer)-based protein array, in the presence and absence of three different inflammatory cytokines (IL-17, TNF and IFN-&gamma;). Expression of 13 different APPs was altered in response to IL-17, TNF or IFN-&gamma;. Independent validations of selected proteins from the proteomics screen i.e., those that were significantly enhanced by &gt;2-fold change (p &lt; 0.01) using western blots conclusively demonstrated that inflammatory cytokines alter the expression of APPs differentially. For example, the abundance of cathepsin S was enhanced by only IFN-&gamma;, whereas lipocalin-2 was increased by IL-17 alone. Abundance of elafin increased in presence of IL-17 or TNF, but decreased in response to IFN-&gamma;. Whereas the abundance of cathepsin V decreased following stimulation with IL-17, TNF and IFN-&gamma;. The results of this study demonstrate that inflammatory cytokines alter the expression of APPs disparately. This suggests that the composition of the inflammatory cytokine milieu may influence APPs abundance and thus alter the processes required for infection control and regulation of inflammation in the lungs

IL-1β production.

<p>Human macrophage-like THP-1 cells were exposed to amphiphiles <b>4–11</b> and <b>14–21</b>, for twenty-four hours. TC supernatants were monitored for IL-1β by ELISA, with results shown in pg/mL. Studies were performed in two independent biological replicates with two technical replicate each, with the data here presented as the mean plus sem. Inset: Expanded results for the negative control and amphiphiles <b>4–7</b> at 5 µM and 10 µM.</p