The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes

Finja C Hansen; Martina Kalle-Brune; Mariena J A van der Plas; Ann-Charlotte Strömdahl; Martin Malmsten; Matthias Mörgelin; Artur Schmidtchen

doi:10.4049/jimmunol.1403009

The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes

Finja C Hansen, Martina Kalle-Brune, Mariena J A van der Plas, Ann-Charlotte Strömdahl, Martin Malmsten, Matthias Mörgelin, Artur Schmidtchen

29 Citationer (Scopus)

Abstract

Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4- and TLR2-induced NF-κB activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38α and JNK1/2/3. FACS and electron microscopy analyses showed that GKY25 interferes with TLR4/myeloid differentiation protein-2 dimerization. The results demonstrate a previously undisclosed activity of the host defense peptide GKY25, based on combined LPS and cell interactions leading to inhibition of TLR4 dimerization and subsequent reduction of NF-κB activity and proinflammatory cytokine production in monocytes and macrophages.

Originalsprog	Engelsk
Tidsskrift	Journal of immunology (Baltimore, Md. : 1950)
Vol/bind	194
Udgave nummer	11
Sider (fra-til)	5397-406
Antal sider	10
ISSN	0022-1767
DOI	https://doi.org/10.4049/jimmunol.1403009
Status	Udgivet - 1 jun. 2015

Adgang til dokumentet

10.4049/jimmunol.1403009

5397.full.pdfForlagets udgivne version, 2,43 MB

https://www.jimmunol.org/content/jimmunol/194/11/5397.full.pdf

Citationsformater

Hansen, F. C., Kalle-Brune, M., van der Plas, M. J. A., Strömdahl, A-C., Malmsten, M., Mörgelin, M., & Schmidtchen, A. (2015). The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes. Journal of immunology (Baltimore, Md. : 1950), 194(11), 5397-406. https://doi.org/10.4049/jimmunol.1403009

The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes. / Hansen, Finja C; Kalle-Brune, Martina; van der Plas, Mariena J A et al.

I: Journal of immunology (Baltimore, Md. : 1950), Bind 194, Nr. 11, 01.06.2015, s. 5397-406.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Hansen, FC, Kalle-Brune, M, van der Plas, MJA, Strömdahl, A-C, Malmsten, M, Mörgelin, M & Schmidtchen, A 2015, 'The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes', Journal of immunology (Baltimore, Md. : 1950), bind 194, nr. 11, s. 5397-406. https://doi.org/10.4049/jimmunol.1403009

@article{f25c4c51420f42dd922e4936c7685ee7,

title = "The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes",

abstract = "Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4- and TLR2-induced NF-κB activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38α and JNK1/2/3. FACS and electron microscopy analyses showed that GKY25 interferes with TLR4/myeloid differentiation protein-2 dimerization. The results demonstrate a previously undisclosed activity of the host defense peptide GKY25, based on combined LPS and cell interactions leading to inhibition of TLR4 dimerization and subsequent reduction of NF-κB activity and proinflammatory cytokine production in monocytes and macrophages.",

keywords = "Amino Acid Sequence, Animals, Antimicrobial Cationic Peptides, Cell Line, Cytokines, Enzyme Activation, Humans, JNK Mitogen-Activated Protein Kinases, Lipopolysaccharides, Lymphocyte Antigen 96, Macrophages, Male, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 14, Molecular Sequence Data, Monocytes, NF-kappa B, Peptide Fragments, Phosphorylation, Protein Multimerization, Signal Transduction, Thrombin, Toll-Like Receptor 2, Toll-Like Receptor 4, Journal Article, Research Support, Non-U.S. Gov't",

author = "Hansen, {Finja C} and Martina Kalle-Brune and {van der Plas}, {Mariena J A} and Ann-Charlotte Str{\"o}mdahl and Martin Malmsten and Matthias M{\"o}rgelin and Artur Schmidtchen",

note = "Copyright {\textcopyright} 2015 by The American Association of Immunologists, Inc.",

year = "2015",

month = jun,

day = "1",

doi = "10.4049/jimmunol.1403009",

language = "English",

volume = "194",

pages = "5397--406",

journal = "Journal of Immunology",

issn = "0022-1767",

publisher = "American Association of Immunologists",

number = "11",

}

TY - JOUR

T1 - The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes

AU - Hansen, Finja C

AU - Kalle-Brune, Martina

AU - van der Plas, Mariena J A

AU - Strömdahl, Ann-Charlotte

AU - Malmsten, Martin

AU - Mörgelin, Matthias

AU - Schmidtchen, Artur

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4- and TLR2-induced NF-κB activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38α and JNK1/2/3. FACS and electron microscopy analyses showed that GKY25 interferes with TLR4/myeloid differentiation protein-2 dimerization. The results demonstrate a previously undisclosed activity of the host defense peptide GKY25, based on combined LPS and cell interactions leading to inhibition of TLR4 dimerization and subsequent reduction of NF-κB activity and proinflammatory cytokine production in monocytes and macrophages.

AB - Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4- and TLR2-induced NF-κB activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38α and JNK1/2/3. FACS and electron microscopy analyses showed that GKY25 interferes with TLR4/myeloid differentiation protein-2 dimerization. The results demonstrate a previously undisclosed activity of the host defense peptide GKY25, based on combined LPS and cell interactions leading to inhibition of TLR4 dimerization and subsequent reduction of NF-κB activity and proinflammatory cytokine production in monocytes and macrophages.

KW - Amino Acid Sequence

KW - Animals

KW - Antimicrobial Cationic Peptides

KW - Cell Line

KW - Cytokines

KW - Enzyme Activation

KW - Humans

KW - JNK Mitogen-Activated Protein Kinases

KW - Lipopolysaccharides

KW - Lymphocyte Antigen 96

KW - Macrophages

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mitogen-Activated Protein Kinase 14

KW - Molecular Sequence Data

KW - Monocytes

KW - NF-kappa B

KW - Peptide Fragments

KW - Phosphorylation

KW - Protein Multimerization

KW - Signal Transduction

KW - Thrombin

KW - Toll-Like Receptor 2

KW - Toll-Like Receptor 4

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.4049/jimmunol.1403009

DO - 10.4049/jimmunol.1403009

M3 - Journal article

C2 - 25911750

SN - 0022-1767

VL - 194

SP - 5397

EP - 5406

JO - Journal of Immunology

JF - Journal of Immunology

IS - 11

ER -

The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater