Neutrophil Elastase Modulates Cytokine Expression

Benabid, Rym; Wartelle, Julien; Malleret, Laurette; Guyot, Nicolas; Gangloff, Sophie C.; Lebargy, F.; Belaaouaj, Abderrazzaq

doi:10.1074/jbc.m112.361352

Cited by 67 publications

(38 citation statements)

References 64 publications

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“…The reported sizes of TLR4 fragments were different, suggesting that different enzymes may be involved in this process. So far, neutrophil elastase and prostasin (a serine protease) have been identified to cleave the extracellular region of TLR4 [25, 26]. The present study clearly demonstrates that 1,25D 3 causes ectodomain shedding of TLR4.…”

Section: Discussionsupporting

confidence: 67%

“…In HepG2 cells [26], the ectodomain cleavage of TLR4 mediated by the serine protease prostasin was also shown to decrease the receptor activity. In contrast, the ectodomain cleavage of TLR4 mediated by neutrophil elastase in macrophage was accompanied by an increased production of inflammatory cytokines [25]. However, it is not clear whether the stimulatory effect on cytokine production was caused by ectodomain shedding of TLR4 or by other unknown mechanisms including secondary mediators produced by neutrophil elastase.…”

Section: Discussionmentioning

confidence: 99%

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1,25-Dihydroxyvitamin D3 Attenuates the Effects of Lipopolysaccharide by Causing ADAM10-Dependent Ectodomain Shedding of Toll-Like Receptor 4

Yang

Kim

Han

et al. 2017

Cell Physiol Biochem

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Background/Aims: We investigated how 1,25-dihydroxyvitamin D₃ (1,25D₃) inhibits the effects of lipopolysaccharide (LPS) in human aortic endothelial cells. Methods: Cellular signaling was explored by determination of protein abundance with Western blot, measurement of cytosolic Ca²⁺ concentration and immunofluorescence staining for a disintegrin and metalloprotease 10 (ADAM10). Results: LPS stimulated the expression of intercellular adhesion molecule 1 (ICAM-1) through toll-like receptor 4 (TLR4) and subsequent activation of p38 mitogen-activated protein kinase (p38 MAPK). Pretreatment with 1,25D₃ attenuated LPS-induced p38 MAPK activation and ICAM-1 expression by causing ectodomain shedding of TLR4. This effect of 1,25D₃ depended on its ability to induce a rapid extracellular Ca²⁺ influx through L-type calcium channels because the ectodomain shedding was prevented by the absence of extracellular Ca²⁺ or the presence of verapamil. TLR4 ectodomain shedding was also induced by Bay K8644 (L-type calcium channel agonist). Both 1,25D₃ and Bay K8644 caused extracellular Ca²⁺ influx-dependent ADAM10 translocation to the cell surface. Depletion of ADAM10 by siRNA transfection prevented 1,25D₃- and Bay K8644-induced ectodomain shedding of TLR4, and abolished the inhibitory effect of 1,25D₃ on LPS-induced ICAM-1 expression. Conclusion: 1,25D₃ causes ectodomain shedding of TLR4 and thereby decreases the responsiveness of cells to LPS. ADAM10, activated by extracellular Ca²⁺ influx, was implicated in the ectodomain cleavage of TLR4.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 Attenuates the Effects of Lipopolysaccharide by Causing ADAM10-Dependent Ectodomain Shedding of Toll-Like Receptor 4

Yang

Kim

Han

et al. 2017

Cell Physiol Biochem

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“…Several possible mechanisms of PMN-driven atherogenesis and plaque destabilization have been proposed [ 15 , 16 ] such as the production of mediators which contribute to ATH. PMN are the exclusive producers of the enzyme elastase [ 17 ], which contribute to matrix degradation and weakening of the vessel wall associated with complications like aneurysm formation and plaque rupture [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Production of IL-8, VEGF and Elastase by Circulating and Intraplaque Neutrophils in Patients with Carotid Atherosclerosis

et al. 2015

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ObjectivesPolymorphonuclear neutrophils (PMN) in atherosclerotic plaques have been identified only recently, and their contribution to plaque development is not yet fully understood. In this study, production of elastase, interleukin (IL)-8 and vascular endothelial growth factor (VEGF) by PMN was investigated in subjects with carotid stenosis undergoing carotid endarterectomy (CEA).MethodsThe study enrolled 50 patients (Pts) and 10 healthy subjects (HS). Circulating PMN (cPMN) isolated from venous blood (in both Pts and HS) and from plaques (pPMN, in Pts) were cultured, alone or with 0.1 μM fMLP. Elastase, IL-8 and VEGF mRNA were analyzed by real-time PCR. In CEA specimens, PMN were localized by immunohistochemistry.ResultsIn both Pts cPMN and pPMN, IL-8 mRNA was higher at rest but lower after fMLP (P<0.01 vs HS), and VEGF mRNA was higher both at rest and after fMLP (P<0.01 vs HS), while elastase mRNA was not significantly different. On the contrary, protein production was always higher in cPMN of HS with respect to values measured in cells of Pts. In CEA specimens, CD66b+ cells localized to areas with massive plaque formation close to neovessels. Pts with soft and mix plaques, as defined by computed tomography, did not differ in cPMN or pPMN IL-8, VEGF or elastase mRNA, or in intraplaque CD66b+ cell density. However, Pts with soft plaques had higher white blood cell count due to increased PMN.ConclusionsIn Pts with carotid plaques, both circulating and intraplaque PMN produce IL-8, VEGF and elastase, which are crucial for plaque development and progression. These findings suggest mechanistic explanations to the reported correlation between PMN count and cardiovascular mortality in carotid ATH.

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“…Excitingly, we found that Bldesin had apparent inhibitory activities on serine protease chymotrypsin and elastase, and 2500 nM Bldesin inhibited over 40% chymotrypsin activity. These results indicated that pathogenic fungus‐derived defensin Bldesin is an important serine protease inhibitor and might play potential roles in the defense of host serine protease system …”

Section: Resultsmentioning

confidence: 84%

Bldesin, the first functionally characterized pathogenic fungus defensin with Kv1.3 channel and chymotrypsin inhibitory activities

Luo

Zhu

et al. 2018

J Biochem & Molecular Tox

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Fungus defensin is a kind of important natural peptide resource, such as plectasin from the soil fungus Pseudoplectania nigrella with potential application in the antimicrobial peptide lead drug discovery. Here, a fungus defensin named Bldesin with Kv1.3 channel and serine protease inhibitory activities was first explored. By GST-Bldesin fusion expression and enterokinase cleaving strategy, recombinant Bldesin was obtained successfully. Antimicrobial assays showed that Bldesin had potent activity against Grampositive Staphylococcus aureus, but had no effect on Gram-negative Escherichia coli.Electrophysiological experiments showed that Bldesin had Kv1.3 channel inhibitory activity. Serine protease inhibitory associated experiments showed that Bldesin had unique chymotrypsin protease inhibitory, elastase protease inhibitory, and serine protease-associated coagulation inhibitory activities. To the best of our knowledge, Bldesin is the first functionally characterized pathogenic fungus defensin with Kv1.3 channel and chymotrypsin inhibitory activities and highlighted novel pharmacological effects of fungus-derived defensin peptides.

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Neutrophil Elastase Modulates Cytokine Expression

Cited by 67 publications

References 64 publications

1,25-Dihydroxyvitamin D3 Attenuates the Effects of Lipopolysaccharide by Causing ADAM10-Dependent Ectodomain Shedding of Toll-Like Receptor 4

1,25-Dihydroxyvitamin D3 Attenuates the Effects of Lipopolysaccharide by Causing ADAM10-Dependent Ectodomain Shedding of Toll-Like Receptor 4

Production of IL-8, VEGF and Elastase by Circulating and Intraplaque Neutrophils in Patients with Carotid Atherosclerosis

Bldesin, the first functionally characterized pathogenic fungus defensin with Kv1.3 channel and chymotrypsin inhibitory activities

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