Antimicrobial peptides and endotoxin inhibit cytokine and nitric oxide release but amplify respiratory burst response in human and murine macrophages

Zughaier, Susu M.; Shafer, William M.; Stephens, David S.

doi:10.1111/j.1462-5822.2005.00549.x

Cited by 115 publications

(76 citation statements)

References 74 publications

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“…1E). This finding is in agreement with several studies showing inactivation of the antibacterial function of LL-37 by LPS (35)(36)(37)(38)(39). It is interesting to note that the elastic modulus of A549 cells treated with a premixed solution of LPS and LL-37 is significantly lower than the elastic modulus of cells treated with either agonist separately.…”

Section: Ll-37 Increases the Stiffness Of A549 And Primary Human Lungsupporting

confidence: 81%

Cathelicidin LL-37 Increases Lung Epithelial Cell Stiffness, Decreases Transepithelial Permeability, and Prevents Epithelial Invasion by Pseudomonas aeruginosa

Byfield

Kowalski

Cruz

et al. 2011

The Journal of Immunology

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In addition to its antibacterial activity, the cathelicidin-derived LL-37 peptide induces multiple immunomodulatory effects on host cells. Atomic force microscopy, F-actin staining with phalloidin, passage of FITC-conjugated dextran through a monolayer of lung epithelial cells, and assessment of bacterial outgrowth from cells subjected to Pseudomonas aeruginosa infection were used to determine LL-37’s effect on epithelial cell mechanical properties, permeability, and bacteria uptake. A concentration-dependent increase in stiffness and F-actin content in the cortical region of A549 cells and primary human lung epithelial cells was observed after treatment with LL-37 (0.5–5 μM), sphingosine 1-phosphate (1 μM), or LPS (1 μg/ml) or infection with PAO1 bacteria. Other cationic peptides, such as RK-31, KR-20, or WLBU2, and the antibacterial cationic steroid CSA-13 did not reproduce the effect of LL-37. A549 cell pretreatment with WRW4, an antagonist of the transmembrane formyl peptide receptor-like 1 protein attenuated LL-37’s ability to increase cell stiffness. The LL-37–mediated increase in cell stiffness was accompanied by a decrease in permeability and P. aeruginosa uptake by a confluent monolayer of polarized normal human bronchial epithelial cells. These results suggested that the antibacterial effect of LL-37 involves an LL-37–dependent increase in cell stiffness that prevents epithelial invasion by bacteria.

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Section: Ll-37 Increases the Stiffness Of A549 And Primary Human Lungsupporting

confidence: 81%

Cathelicidin LL-37 Increases Lung Epithelial Cell Stiffness, Decreases Transepithelial Permeability, and Prevents Epithelial Invasion by Pseudomonas aeruginosa

Byfield

Kowalski

Cruz

et al. 2011

The Journal of Immunology

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“…This effect may be due to the formation of large LPSpeptide aggregates that can be cross-linked by the excessive amount of added peptide and may increase the internalization of LPS. Similar effect on the enhancement of cell activation has been observed for some other cationic antimicrobial peptides (46).…”

Section: Identification Of the Lps-binding Segment Of Marckssupporting

confidence: 60%

MARCKS as a Negative Regulator of Lipopolysaccharide Signaling

Manček-Keber

Benčina

Japelj

et al. 2012

The Journal of Immunology

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Myristoylated alanine-rich C kinase substrate (MARCKS) is an intrinsically unfolded protein with a conserved cationic effector domain, which mediates the cross-talk between several signal transduction pathways. Transcription of MARCKS is increased by stimulation with bacterial LPS. We determined that MARCKS and MARCKS-related protein specifically bind to LPS and that the addition of the MARCKS effector peptide inhibited LPS-induced production of TNF-α in mononuclear cells. The LPS binding site within the effector domain of MARCKS was narrowed down to a heptapeptide that binds to LPS in an extended conformation as determined by nuclear magnetic resonance spectroscopy. After LPS stimulation, MARCKS moved from the plasma membrane to FYVE-positive endosomes, where it colocalized with LPS. MARCKS-deficient mouse embryonic fibroblasts (MEFs) responded to LPS with increased IL-6 production compared with the matched wild-type MEFs. Similarly, small interfering RNA knockdown of MARCKS also increased LPS signaling, whereas overexpression of MARCKS inhibited LPS signaling. TLR4 signaling was enhanced by the ablation of MARCKS, which had no effect on stimulation by TLR2, TLR3, and TLR5 agonists. These findings demonstrate that MARCKS contributes to the negative regulation of the cellular response to LPS.

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“…␣-Defensins are stored almost exclusively in a subset of the azurophilic granules of neutrophils (40,41). In vitro, ␣-defensins have been implicated in the activation of macrophages (18,36), the production of TNF␣ (36), increased expression of scavenger receptors, and the activation of endothelial cells with release of reactive oxygen species (18,42,43). However, the absence of ␣-defensins in murine PMNs has precluded an assessment of their effects on lipoprotein metabolism and the development of early athero- sclerotic lesions in this species, a gap in knowledge we sought to address in this study.…”

Section: Discussionmentioning

confidence: 88%

α-Defensins Induce a Post-translational Modification of Low Density Lipoprotein (LDL) That Promotes Atherosclerosis at Normal Levels of Plasma Cholesterol

Abu‐Fanne¹,

Maraga²,

Abd‐Elrahman

et al. 2016

Journal of Biological Chemistry

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Approximately one-half of the patients who develop clinical atherosclerosis have normal or only modest elevations in plasma lipids, indicating that additional mechanisms contribute to pathogenesis. In view of increasing evidence that inflammation contributes to atherogenesis, we studied the effect of human neutrophil ␣-defensins on low density lipoprotein (LDL) trafficking, metabolism, vascular deposition, and atherogenesis using transgenic mice expressing human ␣-defensins in their polymorphonuclear leukocytes (Def ؉/؉ ). Accelerated Def Atherosclerosis and its thrombotic sequel, "atherothrombosis," are likely to remain the predominant cause of death in "developed" countries for decades to come. The etiology of this syndrome is multifactorial, and current predictors provide an incomplete estimate of the risk and opportunity for intervention. In a pooled analysis of over 87,000 persons with diagnosed coronary heart disease, one in five lacked any of the conventional risk factors: hypertension, smoking, high cholesterol, or diabetes (1). Furthermore, half of all cardiovascular events occur in patients with normal lipid levels (2). These data reveal the need to identify and mitigate as yet undescribed, but clinically relevant, risk factors for cardiovascular disease beyond those targeted in current practice.This problem is compounded by the lack of animal models that closely simulate human disease. Animal models used to study atherosclerosis, including its hyperlipidemic (3, 4) and inflammatory (5) components, are often characterized by striking elevations in plasma cholesterol, reaching plasma concentrations of 1500 -2200 mg/dl in LDLR Ϫ/Ϫ and 400 -450 mg/dl in ApoE Ϫ/Ϫ mice fed a high fat diet (3, 4), and most of the cholesterol is found in the VLDL fraction (3, 4). Neither these levels of lipids nor this distribution of lipoproteins is representative of findings in the vast majority of patients with atherosclerosis. Thus, there continues to be a need for new models to identify novel risk factors and novel approaches to intervention.We have identified human ␣-defensins 1-4, also known as human neutrophil peptides (HNPs), 2 as potentially having a role in the development of atherosclerosis. ␣-Defensins are antimicrobial proteins that constitute ϳ5% of the total protein in polymorphonuclear leukocytes (PMNs). ␣-Defensins are released from a subset of azurophilic granules when the PMNs are activated by a variety of agonists (6, 7). ␣-Defensins are abundant in human atherosclerotic coronary and carotid arteries (8, 9), and there is a significant correlation between the deposition of ␣-defensins in skin tissue and the severity of coronary artery disease (10). ␣-Defensins inhibit the degradation of low density lipoprotein (LDL) and Lp(a) by vascular cells (11), increase their binding and retention in extracellular matrix (12), and inhibit tissue-type plasminogen activator (tPA)-mediated fibrinolysis (13, 14).These observations have been confirmed and extended by others. Increased plasma levels of ␣-defensins are assoc...

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Antimicrobial peptides and endotoxin inhibit cytokine and nitric oxide release but amplify respiratory burst response in human and murine macrophages

Cited by 115 publications

References 74 publications

Cathelicidin LL-37 Increases Lung Epithelial Cell Stiffness, Decreases Transepithelial Permeability, and Prevents Epithelial Invasion by Pseudomonas aeruginosa

Cathelicidin LL-37 Increases Lung Epithelial Cell Stiffness, Decreases Transepithelial Permeability, and Prevents Epithelial Invasion by Pseudomonas aeruginosa

MARCKS as a Negative Regulator of Lipopolysaccharide Signaling

α-Defensins Induce a Post-translational Modification of Low Density Lipoprotein (LDL) That Promotes Atherosclerosis at Normal Levels of Plasma Cholesterol

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