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Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase

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Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase. / Langer, Florian; Spath, Brigitte; Fischer, Cornelia; Stolz, Moritz; Ayuketang, Francis Ayuk; Kröger, Nicolaus-Martin; Bokemeyer, Carsten; Ruf, Wolfram.

In: BLOOD, Vol. 121, No. 12, 21.03.2013, p. 2324-35.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Langer, F, Spath, B, Fischer, C, Stolz, M, Ayuketang, FA, Kröger, N-M, Bokemeyer, C & Ruf, W 2013, 'Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase', BLOOD, vol. 121, no. 12, pp. 2324-35. https://doi.org/10.1182/blood-2012-10-460493

APA

Langer, F., Spath, B., Fischer, C., Stolz, M., Ayuketang, F. A., Kröger, N-M., Bokemeyer, C., & Ruf, W. (2013). Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase. BLOOD, 121(12), 2324-35. https://doi.org/10.1182/blood-2012-10-460493

Vancouver

Langer F, Spath B, Fischer C, Stolz M, Ayuketang FA, Kröger N-M et al. Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase. BLOOD. 2013 Mar 21;121(12):2324-35. https://doi.org/10.1182/blood-2012-10-460493

Bibtex

@article{b95e72c04a1745c4a22bb0ed52de1375,
title = "Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase",
abstract = "Lymphocyte depletion with antithymocyte globulin (ATG) can be complicated by systemic coagulation activation. We found that ATG activated tissue factor procoagulant activity (TF PCA) on monocytic cells more potently than other stimuli that decrypt TF, including cell disruption, TF pathway inhibitor inhibition, and calcium ionophore treatment. Induction of TF PCA by ATG was dependent on lipid raft integrity and complement activation. We showed that ATG-mediated TF activation required complement activation until assembly of the C5b-7 membrane insertion complex, but not lytic pore formation by the membrane attack complex C5b-9. Consistently, induction of TF PCA by ATG did not require maximal phosphatidylserine membrane exposure and was not correlated with the magnitude of complement-induced lytic cell injury. Blockade of free thiols, an inhibitory monoclonal antibody to protein disulfide isomerase (PDI), and the small-molecule PDI antagonist quercetin-3-rutinoside prevented ATG-mediated TF activation, and C5 complement activation resulted in oxidation of cell surface PDI. This rapid and potent mechanism of cellular TF activation represents a novel connection between the complement system and cell surface PDI-mediated thiol-disulfide exchange. Delineation of this clinically relevant mechanism of activation of the extrinsic coagulation pathway during immunosuppressive therapy with ATG may have broader implications for vascular thrombosis associated with inflammatory disorders.",
keywords = "Antilymphocyte Serum, Cells, Cultured, Complement Activation, Complement C5, Disulfides, Drug Evaluation, Preclinical, Humans, Membrane Microdomains, Models, Biological, Monocytes, Oxidation-Reduction, Protein Disulfide-Isomerases, Thromboplastin, Time Factors",
author = "Florian Langer and Brigitte Spath and Cornelia Fischer and Moritz Stolz and Ayuketang, {Francis Ayuk} and Nicolaus-Martin Kr{\"o}ger and Carsten Bokemeyer and Wolfram Ruf",
year = "2013",
month = mar,
day = "21",
doi = "10.1182/blood-2012-10-460493",
language = "English",
volume = "121",
pages = "2324--35",
journal = "BLOOD",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "12",

}

RIS

TY - JOUR

T1 - Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase

AU - Langer, Florian

AU - Spath, Brigitte

AU - Fischer, Cornelia

AU - Stolz, Moritz

AU - Ayuketang, Francis Ayuk

AU - Kröger, Nicolaus-Martin

AU - Bokemeyer, Carsten

AU - Ruf, Wolfram

PY - 2013/3/21

Y1 - 2013/3/21

N2 - Lymphocyte depletion with antithymocyte globulin (ATG) can be complicated by systemic coagulation activation. We found that ATG activated tissue factor procoagulant activity (TF PCA) on monocytic cells more potently than other stimuli that decrypt TF, including cell disruption, TF pathway inhibitor inhibition, and calcium ionophore treatment. Induction of TF PCA by ATG was dependent on lipid raft integrity and complement activation. We showed that ATG-mediated TF activation required complement activation until assembly of the C5b-7 membrane insertion complex, but not lytic pore formation by the membrane attack complex C5b-9. Consistently, induction of TF PCA by ATG did not require maximal phosphatidylserine membrane exposure and was not correlated with the magnitude of complement-induced lytic cell injury. Blockade of free thiols, an inhibitory monoclonal antibody to protein disulfide isomerase (PDI), and the small-molecule PDI antagonist quercetin-3-rutinoside prevented ATG-mediated TF activation, and C5 complement activation resulted in oxidation of cell surface PDI. This rapid and potent mechanism of cellular TF activation represents a novel connection between the complement system and cell surface PDI-mediated thiol-disulfide exchange. Delineation of this clinically relevant mechanism of activation of the extrinsic coagulation pathway during immunosuppressive therapy with ATG may have broader implications for vascular thrombosis associated with inflammatory disorders.

AB - Lymphocyte depletion with antithymocyte globulin (ATG) can be complicated by systemic coagulation activation. We found that ATG activated tissue factor procoagulant activity (TF PCA) on monocytic cells more potently than other stimuli that decrypt TF, including cell disruption, TF pathway inhibitor inhibition, and calcium ionophore treatment. Induction of TF PCA by ATG was dependent on lipid raft integrity and complement activation. We showed that ATG-mediated TF activation required complement activation until assembly of the C5b-7 membrane insertion complex, but not lytic pore formation by the membrane attack complex C5b-9. Consistently, induction of TF PCA by ATG did not require maximal phosphatidylserine membrane exposure and was not correlated with the magnitude of complement-induced lytic cell injury. Blockade of free thiols, an inhibitory monoclonal antibody to protein disulfide isomerase (PDI), and the small-molecule PDI antagonist quercetin-3-rutinoside prevented ATG-mediated TF activation, and C5 complement activation resulted in oxidation of cell surface PDI. This rapid and potent mechanism of cellular TF activation represents a novel connection between the complement system and cell surface PDI-mediated thiol-disulfide exchange. Delineation of this clinically relevant mechanism of activation of the extrinsic coagulation pathway during immunosuppressive therapy with ATG may have broader implications for vascular thrombosis associated with inflammatory disorders.

KW - Antilymphocyte Serum

KW - Cells, Cultured

KW - Complement Activation

KW - Complement C5

KW - Disulfides

KW - Drug Evaluation, Preclinical

KW - Humans

KW - Membrane Microdomains

KW - Models, Biological

KW - Monocytes

KW - Oxidation-Reduction

KW - Protein Disulfide-Isomerases

KW - Thromboplastin

KW - Time Factors

U2 - 10.1182/blood-2012-10-460493

DO - 10.1182/blood-2012-10-460493

M3 - SCORING: Journal article

C2 - 23315166

VL - 121

SP - 2324

EP - 2335

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 12

ER -