Adenoviral Gene Delivery of Elafin and Secretory Leukocyte Protease Inhibitor Attenuates NF-κB-Dependent Inflammatory Responses of Human Endothelial Cells and Macrophages to Atherogenic Stimuli

Henriksen, Peter; Hitt, Mary; Xing, Zhou; Wang, Jun; Haslett, Chris; Riemersma, Rudolph A.; Webb, David J.; Kotelevtsev, Yuri; Sallenave, Jean-Michel

doi:10.4049/jimmunol.172.7.4535

Cited by 134 publications

(127 citation statements)

References 64 publications

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“…However, it is worth noting that NE regulation of the inflammatory response is cell content dependent. Different studies showed that NE increases IL‐8 in endothelial cells,44 while NE suppresses IL‐8 expression in SMCs 45. Evidence has also suggested that NE may function as a negative regulator of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Wen

Chen

et al. 2018

JAHA

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BackgroundTo investigate whether neutrophil elastase (NE) plays a causal role in atherosclerosis, and the molecular mechanisms involved.Methods and Results NE genetic–deficient mice (Apolipoprotein E−/−/NE −/− mice), bone marrow transplantation, and a specific NE inhibitor (GW311616A) were employed in this study to establish the causal role of NE in atherosclerosis. Aortic expression of NE mRNA and plasma NE activity was significantly increased in high‐fat diet (HFD)–fed wild‐type (WT) (Apolipoprotein E−/−) mice but, as expected, not in NE‐deficient mice. Selective NE knockout markedly reduced HFD‐induced atherosclerosis and significantly increased indicators of atherosclerotic plaque stability. While plasma lipid profiles were not affected by NE deficiency, decreased levels of circulating proinflammatory cytokines and inflammatory monocytes (Ly6Chi/CD11b+) were observed in NE‐deficient mice fed with an HFD for 12 weeks as compared with WT. Bone marrow reconstitution of WT mice with NE −/− bone marrow cells significantly reduced HFD‐induced atherosclerosis, while bone marrow reconstitution of NE −/− mice with WT bone marrow cells restored the pathological features of atherosclerotic plaques induced by HFD in NE‐deficient mice. In line with these findings, pharmacological inhibition of NE in WT mice through oral administration of NE inhibitor GW311616A also significantly reduced atherosclerosis. Mechanistically, we demonstrated that NE promotes foam cell formation by increasing ATP‐binding cassette transporter ABCA1 protein degradation and inhibiting macrophage cholesterol efflux.ConclusionsWe outlined a pathogenic role for NE in foam cell formation and atherosclerosis development. Consequently, inhibition of NE may represent a potential therapeutic approach to treating cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Wen

Chen

et al. 2018

JAHA

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“…Some of the antiinflammatory effects of the anti-leukoproteinases may involve inhibition of NFKB. In vitro, overexpression of SLPI suppresses NFKB activation (Jin et al 1997, Sano et al 2003, Henriksen et al 2004. It can prevent proteosome-dependent IkBb degradation (Lentsch et al 1999) and also directly bind to NFKB consensus sites on DNA, inhibiting transcription (Taggart et al 2005).…”

Section: Natural Antimicrobial Peptides (Naps)mentioning

confidence: 99%

Innate immunity and disorders of the female reproductive tract

Horne¹,

Stock²,

King³

2008

Reproduction

136

129

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Sexually transmitted infections, and their associated sequelae, such as tubal infertility, ectopic pregnancy and preterm labour, are a major worldwide health problem. Chlamydia trachomatis infection is thought to be the leading global cause of tubal infertility and tubal ectopic pregnancy. Preterm birth occurs in around 10% of all deliveries, and nearly 30% of preterm deliveries are associated with intrauterine infection. The mucosal innate immune system of the female reproductive tract has evolved to eliminate such sexually transmitted pathogens whilst maintaining its ability to accommodate specialized physiological functions that include menstruation, fertilization, implantation, pregnancy and parturition. The aim of this review was to describe the role and distribution of key mediators of the innate immune system, the natural antimicrobial peptides (secretory leukocyte protease inhibitor, elafin and the defensins) and the pattern recognition toll-like receptors in the normal female reproductive tract and in the context of these pathological processes.

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“…mRNA expression (data not shown). Intracellular SLPI is known to inhibit TLR 4 signaling by suppressing the activation of NF-B by preventing the degradation of the inhibitory factor IB (32,36,37). To see whether SLPI is involved in suppression of cellular activation in DCs, we compared the level of NF-B p65 activation in LPS-stimulated WT and SLPI Ϫ/Ϫ BM-DCs.…”

Section: Mhciimentioning

confidence: 99%

Secretory Leukoprotease Inhibitor in Mucosal Lymph Node Dendritic Cells Regulates the Threshold for Mucosal Tolerance

Samsom

Marel

Berkel

et al. 2007

The Journal of Immunology

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The notion that the mucosal immune system maintains a tolerogenic response to harmless Ags while continually being challenged with microbial products seems an enigma. The aim of this study was to unravel mechanisms that are involved in regulating the development of tolerance under constant microbial pressure. The tolerogenic response to Ags administered via the nasal mucosa is dependent on the organized lymphoid tissue of the cervical lymph nodes (LN). We show that cervical LN differentially express secretory leukoprotease inhibitor (SLPI) compared with peripheral LN. SLPI was expressed by dendritic cells (DCs) and because SLPI is known to suppress LPS responsiveness, it was hypothesized that its expression in mucosal DCs may be required to regulate cellular activation to microbial products. Indeed, compared with wild-type controls, bone marrow-derived DCs from SLPI−/− mice released more inflammatory cytokines and enhanced T cell proliferation after stimulation with low dose LPS. This increased sensitivity to LPS was accompanied by increased NF-κB p65 activation in SLPI−/− DCs. In vivo, nasal application of OVA with LPS to SLPI−/− mice resulted in enhanced DC activation in the cervical LN reflected by increased costimulatory molecule expression and release of inflammatory cytokines. This led to failure to maintain tolerance to nasal OVA application in the presence of low doses of LPS. We propose that expression of SLPI functions as a rheostat by controlling the level of bacterial stimuli that induce mucosal DC activation. As such, it regulates the quality of the ensuing Ag-specific immune response in the mucosa draining LN.

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Adenoviral Gene Delivery of Elafin and Secretory Leukocyte Protease Inhibitor Attenuates NF-κB-Dependent Inflammatory Responses of Human Endothelial Cells and Macrophages to Atherogenic Stimuli

Cited by 134 publications

References 64 publications

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Innate immunity and disorders of the female reproductive tract

Secretory Leukoprotease Inhibitor in Mucosal Lymph Node Dendritic Cells Regulates the Threshold for Mucosal Tolerance

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