Apolipoprotein A-I Binds and Inhibits the Human Antibacterial/Cytotoxic Peptide LL-37

Wang, Yuqin; Agerberth, Birgitta; Löthgren, Agneta; Almstedt, Annelie; Johansson, Jan

doi:10.1074/jbc.273.50.33115

Cited by 133 publications

(115 citation statements)

References 20 publications

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“…For example, the antimicrobial activities of defensins are inhibited by the presence of physiological salt (17), whereas the cathelicidin LL-37 is inhibited by plasma (18). Other AMPs, such as azurocidin and magainins, are potentiated by acidic conditions likely to occur in biological fluids following oxidative burst response of leukocytes (19).…”

Section: Resultsmentioning

confidence: 99%

Activation of the complement system generates antibacterial peptides

Nordahl

Rydengård

Nyberg

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

211

174

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The complement system represents an evolutionary old and significant part of the innate immune system involved in protection against invading microorganisms. Here, we show that the anaphylatoxin C3a and its inactivated derivative C3a-desArg are antibacterial, demonstrating a previously unknown direct antimicrobial effect of complement activation. The C3a peptide, as well as functional epitopes in the sequence, efficiently killed the Gramnegative bacteria Escherichia coli, Pseudomonas aeruginosa, and the Gram-positive Enterococcus faecalis. In mice, a C3a-derived peptide suppressed infection by Gram-positive Streptococcus pyogenes bacteria. Fluorescence and electron microscopy demonstrated that C3a binds to and induces breaks in bacterial membranes. C3a was also found to induce membrane leakage of liposomes. These findings provide an interesting link between the complement system and antimicrobial peptides, which are two important branches of innate immunity.bacteria ͉ inflammation ͉ innate immunity

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Section: Resultsmentioning

confidence: 99%

Activation of the complement system generates antibacterial peptides

Nordahl

Rydengård

Nyberg

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

211

174

View full text Add to dashboard Cite

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“…The properties of LL-37 have been demonstrated to be altered in the presence of serum (32). In fact, in the absence of serum, moderate concentrations (30 -100 g/ml) of LL-37 and related peptides were cytotoxic toward both prokaryotic and eukaryotic cells (24,33,34). However, in the presence of serum, cytotoxicity toward both cell types was substantially reduced (33,35).…”

Section: Discussionmentioning

confidence: 99%

“…When LL-37 is found in the blood or tissues during the course of infection, it may exist coupled to one or several proteins. The presence of apolipoprotein 1 has been proposed to reduce LL-37-induced cytotoxicity while also inhibiting its antimicrobial functions (24). It will be of interest to determine whether the presence of apolipoprotein can restore the ability of LL-37 to induce signaling in serum-free medium; however, it is not unreasonable to assume that there are multiple components in serum that may interact with the positively charged LL-37.…”

Section: Discussionmentioning

confidence: 99%

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The Human Cationic Peptide LL-37 Induces Activation of the Extracellular Signal-Regulated Kinase and p38 Kinase Pathways in Primary Human Monocytes

Bowdish

Davidson

Speert

et al. 2004

The Journal of Immunology

221

229

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LL-37 is a cationic peptide that is found in the granules of neutrophils and is secreted by epithelial cells from a variety of tissues. Levels of LL-37 in vivo increase upon infection, and its production and secretion are increased upon stimulation with proinflammatory mediators. It has been postulated that LL-37 modulates the immune response by interacting with the effector cells of innate immunity; however, the mechanism of this interaction is unknown. LL-37 induced phosphorylation and activation of the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, in human peripheral blood-derived monocytes and a human bronchial epithelial cell line, but not in B or T lymphocytes. Phosphorylation was not dependent on the G protein-coupled formyl peptide-like receptor 1, which was previously proposed to be the receptor for LL-37-induced chemotaxis on human monocytes and T cells. Activation of ERK1/2 and p38 was markedly increased by the presence of GM-CSF, but not M-CSF. Exposure to LL-37 also led to the activation of Elk-1, a transcription factor that is downstream of and activated by phosphorylated ERK1/2, the up-regulation of various Elk-1-controlled genes, and the transcription and secretion of IL-8. Inhibition of either p38 or ERK1/2 kinases led to a reduction in LL-37-induced IL-8 secretion and inhibition of the transcription of various chemokine genes. The ability of LL-37 to signal through these pathways has broad implications in immunity, monocyte activation, proliferation, and differentiation.

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“…This difference is probably due to lipoproteins present in the culture medium used for growth inhibition assays. As serum components compete with membranes for the binding of membrane-active peptides [45][46][47], they should indeed increase their apparent MICs.…”

Section: Discussionmentioning

confidence: 99%

The antibiotic activity of cationic linear amphipathic peptides: lessons from the action of leucine/lysine copolymers on bacteria of the class Mollicutes

Béven

Castano

Dufourcq

et al. 2003

European Journal of Biochemistry

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Peptides composed of leucyl and lysyl residues (ÔLK peptidesÕ) with different compositions and sequences were compared for their antibacterial activities using cell wall-less bacteria of the class Mollicutes (acholeplasmas, mycoplasmas and spiroplasmas) as targets. The antibacterial activity of the amphipathic a-helical peptides varied with their size, 15 residues being the optimal length, independent of the membrane hydrophobic core thickness and the amount of cholesterol. The 15-residue ideally amphipathic a helix with a +5 positive net charge (KLLKLLLKLLLKLLK) had the strongest antibacterial activity, similar to that of melittin. In contrast, scrambled peptides devoid of amphipathy and the less hydrophobic b-sheeted peptides [(LK) n K], even those 15-residue long, were far less potent than the helical ones. Furthermore, the growth inhibitory activity of the peptides was correlated with their ability to abolish membrane potential. These data are fully consistent with a predominantly flat orientation of LK peptides at the lipid/ water interface and strongly supports that these peptides and probably the linear polycationic amphipathic defence peptides act on bacterial membranes in four main steps according to the ÔcarpetÕ model: (a) interfacial partitioning with accumulation of monomers on the target membrane (limiting step); (b) peptide structural changes (conformation, aggregation, and orientation) induced by interactions with the lipid bilayer (as already shown with liposomes and erythrocytes); (c) plasma membrane permeabilization/ depolarization via a detergent-like effect; and (d) rapid bacterial cell death if the extent of depolarization is maintained above a critical threshold.Keywords: amphipathic peptides; antibacterial activity; bacterial cell death; membrane depolarization; mollicutes.The amphipathic a helix concept helps in understanding the behaviour of very different classes of proteins and peptides, especially those acting on membranes [1][2][3][4]. This concept, which has been useful in the field of peptidic cytotoxins to develop new analogues, and to better understand their mode of action [5][6][7], is still the basis for the rational design of new antimicrobial compounds, i.e. analogues or chimeras of natural products [8], or radically new molecules [9,10].The need to understand their mode of action and improve their efficacy and/or selectivity towards microorganisms led to the synthesis of new active peptides, made possible largely by the progress in solid state synthesis. As a result, a large wealth of information was obtained on many natural peptides endowed with cytotoxic (including antimicrobial) activity. However, answers are still missing regarding: (a) the requirements for optimized activity and selectivity; and (b) the mechanisms of action, especially in bacterial cells. In an effort of rationalization, a minimalistic approach was initiated by the pioneering work of De Grado and Lear [11] using residue substitutions or designing simplified sequences [2,[12][13][14]. Using the very mini...

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Apolipoprotein A-I Binds and Inhibits the Human Antibacterial/Cytotoxic Peptide LL-37

Cited by 133 publications

References 20 publications

Activation of the complement system generates antibacterial peptides

Activation of the complement system generates antibacterial peptides

The Human Cationic Peptide LL-37 Induces Activation of the Extracellular Signal-Regulated Kinase and p38 Kinase Pathways in Primary Human Monocytes

The antibiotic activity of cationic linear amphipathic peptides: lessons from the action of leucine/lysine copolymers on bacteria of the class Mollicutes

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