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Inhibition of protein disulfide isomerase with PACMA-31 regulates monocyte tissue factor through transcriptional and posttranscriptional mechanisms

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Inhibition of protein disulfide isomerase with PACMA-31 regulates monocyte tissue factor through transcriptional and posttranscriptional mechanisms. / Beckmann, Lennart; Mäder, Jonathan; Voigtlaender, Minna; Klingler, Felix; Schulenkorf, Anita; Lehr, Carina; Regenhardt, Judith; Bokemeyer, Carsten; Ruf, Wolfram; Rolling, Christina; Langer, Florian.

in: THROMB RES, Jahrgang 220, 12.2022, S. 48-59.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Beckmann, L, Mäder, J, Voigtlaender, M, Klingler, F, Schulenkorf, A, Lehr, C, Regenhardt, J, Bokemeyer, C, Ruf, W, Rolling, C & Langer, F 2022, 'Inhibition of protein disulfide isomerase with PACMA-31 regulates monocyte tissue factor through transcriptional and posttranscriptional mechanisms', THROMB RES, Jg. 220, S. 48-59. https://doi.org/10.1016/j.thromres.2022.09.024

APA

Beckmann, L., Mäder, J., Voigtlaender, M., Klingler, F., Schulenkorf, A., Lehr, C., Regenhardt, J., Bokemeyer, C., Ruf, W., Rolling, C., & Langer, F. (2022). Inhibition of protein disulfide isomerase with PACMA-31 regulates monocyte tissue factor through transcriptional and posttranscriptional mechanisms. THROMB RES, 220, 48-59. https://doi.org/10.1016/j.thromres.2022.09.024

Vancouver

Beckmann L, Mäder J, Voigtlaender M, Klingler F, Schulenkorf A, Lehr C et al. Inhibition of protein disulfide isomerase with PACMA-31 regulates monocyte tissue factor through transcriptional and posttranscriptional mechanisms. THROMB RES. 2022 Dez;220:48-59. https://doi.org/10.1016/j.thromres.2022.09.024

Bibtex

@article{2066310f33564b30b57b1b1e87d7b59f,
title = "Inhibition of protein disulfide isomerase with PACMA-31 regulates monocyte tissue factor through transcriptional and posttranscriptional mechanisms",
abstract = "INTRODUCTION: Protein disulfide isomerase (PDI) contributes to tissue factor (TF) regulation in monocytes. While bacitracin and quercetin-3-rutinoside mitigate myeloid TF production, the effect of PACMA-31, a more specific PDI inhibitor with distinct pharmacologic properties, remains unclear.MATERIALS AND METHODS: Lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells (PBMCs) or citrate-anticoagulated whole blood was carried out in the presence of PACMA-31 or DMSO vehicle before monocytes were analyzed for TF expression, including antigen, procoagulant activity (PCA) and mRNA, release of IL-6 and TNFα, and LPS-induced signaling pathways.RESULTS: While PACMA-31 alone had no effect, coincubation with LPS and PACMA-31 (25 μM) enhanced LPS-induced monocyte TF production in whole blood. The effect was at least partially regulated on the transcriptional level and could not be explained by increased phosphatidylserine membrane exposure. In contrast, the same PACMA-31 concentrations were cytotoxic in isolated PBMCs. A lower dose of PACMA-31, however, restored the stimulating effect by enhancing IκB-NFκB signaling that also increased the release of IL-6 and TNFα. The protease-activated receptor 2 (PAR2) inhibitor ENMD547 but not TF antibody 10H10 or factor Xa inhibitor rivaroxaban prevented the stimulatory effect of PACMA-31 on inflammatory monocytes. In sharp contrast, short time incubation of LPS-stimulated PBMCs with 25 μM PACMA-31 was non-cytotoxic and significantly inhibited cellular TF PCA but not surface antigen expression.CONCLUSIONS: PACMA-31 regulates monocyte TF in a concentration-dependent manner by opposing transcriptional and posttranscriptional mechanisms. While low concentrations of PACMA-31 augment monocyte TF production by amplifying LPS-dependent PAR2 signaling, high concentrations convert monocyte TF into its non-coagulant state.",
author = "Lennart Beckmann and Jonathan M{\"a}der and Minna Voigtlaender and Felix Klingler and Anita Schulenkorf and Carina Lehr and Judith Regenhardt and Carsten Bokemeyer and Wolfram Ruf and Christina Rolling and Florian Langer",
note = "Copyright {\textcopyright} 2022 Elsevier Ltd. All rights reserved.",
year = "2022",
month = dec,
doi = "10.1016/j.thromres.2022.09.024",
language = "English",
volume = "220",
pages = "48--59",
journal = "THROMB RES",
issn = "0049-3848",
publisher = "Elsevier Limited",

}

RIS

TY - JOUR

T1 - Inhibition of protein disulfide isomerase with PACMA-31 regulates monocyte tissue factor through transcriptional and posttranscriptional mechanisms

AU - Beckmann, Lennart

AU - Mäder, Jonathan

AU - Voigtlaender, Minna

AU - Klingler, Felix

AU - Schulenkorf, Anita

AU - Lehr, Carina

AU - Regenhardt, Judith

AU - Bokemeyer, Carsten

AU - Ruf, Wolfram

AU - Rolling, Christina

AU - Langer, Florian

N1 - Copyright © 2022 Elsevier Ltd. All rights reserved.

PY - 2022/12

Y1 - 2022/12

N2 - INTRODUCTION: Protein disulfide isomerase (PDI) contributes to tissue factor (TF) regulation in monocytes. While bacitracin and quercetin-3-rutinoside mitigate myeloid TF production, the effect of PACMA-31, a more specific PDI inhibitor with distinct pharmacologic properties, remains unclear.MATERIALS AND METHODS: Lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells (PBMCs) or citrate-anticoagulated whole blood was carried out in the presence of PACMA-31 or DMSO vehicle before monocytes were analyzed for TF expression, including antigen, procoagulant activity (PCA) and mRNA, release of IL-6 and TNFα, and LPS-induced signaling pathways.RESULTS: While PACMA-31 alone had no effect, coincubation with LPS and PACMA-31 (25 μM) enhanced LPS-induced monocyte TF production in whole blood. The effect was at least partially regulated on the transcriptional level and could not be explained by increased phosphatidylserine membrane exposure. In contrast, the same PACMA-31 concentrations were cytotoxic in isolated PBMCs. A lower dose of PACMA-31, however, restored the stimulating effect by enhancing IκB-NFκB signaling that also increased the release of IL-6 and TNFα. The protease-activated receptor 2 (PAR2) inhibitor ENMD547 but not TF antibody 10H10 or factor Xa inhibitor rivaroxaban prevented the stimulatory effect of PACMA-31 on inflammatory monocytes. In sharp contrast, short time incubation of LPS-stimulated PBMCs with 25 μM PACMA-31 was non-cytotoxic and significantly inhibited cellular TF PCA but not surface antigen expression.CONCLUSIONS: PACMA-31 regulates monocyte TF in a concentration-dependent manner by opposing transcriptional and posttranscriptional mechanisms. While low concentrations of PACMA-31 augment monocyte TF production by amplifying LPS-dependent PAR2 signaling, high concentrations convert monocyte TF into its non-coagulant state.

AB - INTRODUCTION: Protein disulfide isomerase (PDI) contributes to tissue factor (TF) regulation in monocytes. While bacitracin and quercetin-3-rutinoside mitigate myeloid TF production, the effect of PACMA-31, a more specific PDI inhibitor with distinct pharmacologic properties, remains unclear.MATERIALS AND METHODS: Lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells (PBMCs) or citrate-anticoagulated whole blood was carried out in the presence of PACMA-31 or DMSO vehicle before monocytes were analyzed for TF expression, including antigen, procoagulant activity (PCA) and mRNA, release of IL-6 and TNFα, and LPS-induced signaling pathways.RESULTS: While PACMA-31 alone had no effect, coincubation with LPS and PACMA-31 (25 μM) enhanced LPS-induced monocyte TF production in whole blood. The effect was at least partially regulated on the transcriptional level and could not be explained by increased phosphatidylserine membrane exposure. In contrast, the same PACMA-31 concentrations were cytotoxic in isolated PBMCs. A lower dose of PACMA-31, however, restored the stimulating effect by enhancing IκB-NFκB signaling that also increased the release of IL-6 and TNFα. The protease-activated receptor 2 (PAR2) inhibitor ENMD547 but not TF antibody 10H10 or factor Xa inhibitor rivaroxaban prevented the stimulatory effect of PACMA-31 on inflammatory monocytes. In sharp contrast, short time incubation of LPS-stimulated PBMCs with 25 μM PACMA-31 was non-cytotoxic and significantly inhibited cellular TF PCA but not surface antigen expression.CONCLUSIONS: PACMA-31 regulates monocyte TF in a concentration-dependent manner by opposing transcriptional and posttranscriptional mechanisms. While low concentrations of PACMA-31 augment monocyte TF production by amplifying LPS-dependent PAR2 signaling, high concentrations convert monocyte TF into its non-coagulant state.

U2 - 10.1016/j.thromres.2022.09.024

DO - 10.1016/j.thromres.2022.09.024

M3 - SCORING: Journal article

C2 - 36265413

VL - 220

SP - 48

EP - 59

JO - THROMB RES

JF - THROMB RES

SN - 0049-3848

ER -