Secretory leukocyte protease inhibitor: A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure

Charalambos Gustav Antoniades; Wafa Khamri; Robin D. Abeles; Leonie S. Taams; Evangelos Triantafyllou; Lucia A. Possamai; Christine Bernsmeier; Ragai R. Mitry; Alistair O'Brien; Derek Gilroy; Robert Goldin; Michael Heneghan; Nigel Heaton; Wayel Jassem; William Bernal; Diego Vergani; Yun Ma; Alberto Quaglia; Julia Wendon; Mark Thursz

doi:10.1002/hep.26933

Secretory leukocyte protease inhibitor: A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure

Charalambos Gustav Antoniades^*, Wafa Khamri, Robin D. Abeles, Leonie S. Taams, Evangelos Triantafyllou, Lucia A. Possamai, Christine Bernsmeier, Ragai R. Mitry, Alistair O'Brien, Derek Gilroy, Robert Goldin, Michael Heneghan, Nigel Heaton, Wayel Jassem, William Bernal, Diego Vergani, Yun Ma, Alberto Quaglia, Julia Wendon, Mark Thursz

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Acetaminophen-induced acute liver failure (AALF) is characterized both by activation of innate immune responses and susceptibility to sepsis. Circulating monocytes and hepatic macrophages are central mediators of inflammatory responses and tissue repair processes during human AALF. Secretory leukocyte protease inhibitor (SLPI) modulates monocyte/macrophage function through inhibition of nuclear factor kappa B (NF-κB) signaling. The aims of this study were to establish the role of SLPI in AALF. Circulating levels of SLPI, monocyte cluster of differentiation 163 (CD163), human leukocyte antigen-DR (HLA-DR), and lipopolysaccharide (LPS)-stimulated levels of NF-κBp65, tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were determined in patients with AALF, chronic liver disease, and healthy controls. Immunohistochemistry and multispectral imaging of AALF explant tissue determined the cellular sources of SLPI and hepatic macrophage phenotype. The phenotype and function of monocytes and macrophages was determined following culture with recombinant human (rh)-SLPI, liver homogenates, and plasma derived from AALF patients in the presence and absence of antihuman (α)SLPI. Hepatic and circulatory concentrations of SLPI were elevated in AALF and immunohistochemistry revealed SLPI expression in biliary epithelial cells and within hepatic macrophages (h-mψ) in areas of necrosis. H-mψ and circulating monocytes in AALF exhibited an anti-inflammatory phenotype and functional characteristics; typified by reductions in NF-κBp65, TNF-α, and IL-6 and preserved IL-10 secretion following LPS challenge. Culture of healthy monocytes with AALF liver homogenates, plasma, or rhSLPI induced monocytes with strikingly similar anti-inflammatory characteristics which were reversed by inhibiting the activity of SLPI. Conclusion: SLPI is a pivotal mediator of anti-inflammatory responses in AALF through modulation of monocyte/macrophage function, which may account for the susceptibility to sepsis in AALF.

Original language	English
Pages (from-to)	1564-1576
Number of pages	13
Journal	Hepatology
Volume	59
Issue number	4
Early online date	28 Feb 2014
DOIs	https://doi.org/10.1002/hep.26933
Publication status	Published - 24 Mar 2014

Keywords

LEUKOCYTE PROTEASE INHIBITOR
SECRETORY LEUKOPROTEASE INHIBITOR
LIPOPOLYSACCHARIDE-STIMULATED MACROPHAGES
INFLAMMATORY RESPONSE
PROTEINASE-INHIBITOR
FAILURE
EXPRESSION
HEPATOTOXICITY
PROLIFERATION
ACTIVATION

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/hep.26933

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Antoniades, C. G., Khamri, W., Abeles, R. D., Taams, L. S., Triantafyllou, E., Possamai, L. A., Bernsmeier, C., Mitry, R. R., O'Brien, A., Gilroy, D., Goldin, R., Heneghan, M., Heaton, N., Jassem, W., Bernal, W., Vergani, D., Ma, Y., Quaglia, A., Wendon, J., & Thursz, M. (2014). Secretory leukocyte protease inhibitor: A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure. Hepatology, 59(4), 1564-1576. https://doi.org/10.1002/hep.26933

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title = "Secretory leukocyte protease inhibitor: A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure",

abstract = "Acetaminophen-induced acute liver failure (AALF) is characterized both by activation of innate immune responses and susceptibility to sepsis. Circulating monocytes and hepatic macrophages are central mediators of inflammatory responses and tissue repair processes during human AALF. Secretory leukocyte protease inhibitor (SLPI) modulates monocyte/macrophage function through inhibition of nuclear factor kappa B (NF-κB) signaling. The aims of this study were to establish the role of SLPI in AALF. Circulating levels of SLPI, monocyte cluster of differentiation 163 (CD163), human leukocyte antigen-DR (HLA-DR), and lipopolysaccharide (LPS)-stimulated levels of NF-κBp65, tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were determined in patients with AALF, chronic liver disease, and healthy controls. Immunohistochemistry and multispectral imaging of AALF explant tissue determined the cellular sources of SLPI and hepatic macrophage phenotype. The phenotype and function of monocytes and macrophages was determined following culture with recombinant human (rh)-SLPI, liver homogenates, and plasma derived from AALF patients in the presence and absence of antihuman (α)SLPI. Hepatic and circulatory concentrations of SLPI were elevated in AALF and immunohistochemistry revealed SLPI expression in biliary epithelial cells and within hepatic macrophages (h-mψ) in areas of necrosis. H-mψ and circulating monocytes in AALF exhibited an anti-inflammatory phenotype and functional characteristics; typified by reductions in NF-κBp65, TNF-α, and IL-6 and preserved IL-10 secretion following LPS challenge. Culture of healthy monocytes with AALF liver homogenates, plasma, or rhSLPI induced monocytes with strikingly similar anti-inflammatory characteristics which were reversed by inhibiting the activity of SLPI. Conclusion: SLPI is a pivotal mediator of anti-inflammatory responses in AALF through modulation of monocyte/macrophage function, which may account for the susceptibility to sepsis in AALF.",

keywords = "LEUKOCYTE PROTEASE INHIBITOR, SECRETORY LEUKOPROTEASE INHIBITOR, LIPOPOLYSACCHARIDE-STIMULATED MACROPHAGES, INFLAMMATORY RESPONSE, PROTEINASE-INHIBITOR, FAILURE, EXPRESSION, HEPATOTOXICITY, PROLIFERATION, ACTIVATION",

author = "Antoniades, {Charalambos Gustav} and Wafa Khamri and Abeles, {Robin D.} and Taams, {Leonie S.} and Evangelos Triantafyllou and Possamai, {Lucia A.} and Christine Bernsmeier and Mitry, {Ragai R.} and Alistair O'Brien and Derek Gilroy and Robert Goldin and Michael Heneghan and Nigel Heaton and Wayel Jassem and William Bernal and Diego Vergani and Yun Ma and Alberto Quaglia and Julia Wendon and Mark Thursz",

year = "2014",

month = mar,

day = "24",

doi = "10.1002/hep.26933",

language = "English",

volume = "59",

pages = "1564--1576",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Wolters Kluwer Health",

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Antoniades, CG, Khamri, W, Abeles, RD , Taams, LS , Triantafyllou, E, Possamai, LA, Bernsmeier, C , Mitry, RR, O'Brien, A, Gilroy, D, Goldin, R, Heneghan, M , Heaton, N, Jassem, W, Bernal, W, Vergani, D , Ma, Y, Quaglia, A, Wendon, J & Thursz, M 2014, 'Secretory leukocyte protease inhibitor: A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure', Hepatology, vol. 59, no. 4, pp. 1564-1576. https://doi.org/10.1002/hep.26933

TY - JOUR

T1 - Secretory leukocyte protease inhibitor

T2 - A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure

AU - Antoniades, Charalambos Gustav

AU - Khamri, Wafa

AU - Abeles, Robin D.

AU - Taams, Leonie S.

AU - Triantafyllou, Evangelos

AU - Possamai, Lucia A.

AU - Bernsmeier, Christine

AU - Mitry, Ragai R.

AU - O'Brien, Alistair

AU - Gilroy, Derek

AU - Goldin, Robert

AU - Heneghan, Michael

AU - Heaton, Nigel

AU - Jassem, Wayel

AU - Bernal, William

AU - Vergani, Diego

AU - Ma, Yun

AU - Quaglia, Alberto

AU - Wendon, Julia

AU - Thursz, Mark

PY - 2014/3/24

Y1 - 2014/3/24

N2 - Acetaminophen-induced acute liver failure (AALF) is characterized both by activation of innate immune responses and susceptibility to sepsis. Circulating monocytes and hepatic macrophages are central mediators of inflammatory responses and tissue repair processes during human AALF. Secretory leukocyte protease inhibitor (SLPI) modulates monocyte/macrophage function through inhibition of nuclear factor kappa B (NF-κB) signaling. The aims of this study were to establish the role of SLPI in AALF. Circulating levels of SLPI, monocyte cluster of differentiation 163 (CD163), human leukocyte antigen-DR (HLA-DR), and lipopolysaccharide (LPS)-stimulated levels of NF-κBp65, tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were determined in patients with AALF, chronic liver disease, and healthy controls. Immunohistochemistry and multispectral imaging of AALF explant tissue determined the cellular sources of SLPI and hepatic macrophage phenotype. The phenotype and function of monocytes and macrophages was determined following culture with recombinant human (rh)-SLPI, liver homogenates, and plasma derived from AALF patients in the presence and absence of antihuman (α)SLPI. Hepatic and circulatory concentrations of SLPI were elevated in AALF and immunohistochemistry revealed SLPI expression in biliary epithelial cells and within hepatic macrophages (h-mψ) in areas of necrosis. H-mψ and circulating monocytes in AALF exhibited an anti-inflammatory phenotype and functional characteristics; typified by reductions in NF-κBp65, TNF-α, and IL-6 and preserved IL-10 secretion following LPS challenge. Culture of healthy monocytes with AALF liver homogenates, plasma, or rhSLPI induced monocytes with strikingly similar anti-inflammatory characteristics which were reversed by inhibiting the activity of SLPI. Conclusion: SLPI is a pivotal mediator of anti-inflammatory responses in AALF through modulation of monocyte/macrophage function, which may account for the susceptibility to sepsis in AALF.

AB - Acetaminophen-induced acute liver failure (AALF) is characterized both by activation of innate immune responses and susceptibility to sepsis. Circulating monocytes and hepatic macrophages are central mediators of inflammatory responses and tissue repair processes during human AALF. Secretory leukocyte protease inhibitor (SLPI) modulates monocyte/macrophage function through inhibition of nuclear factor kappa B (NF-κB) signaling. The aims of this study were to establish the role of SLPI in AALF. Circulating levels of SLPI, monocyte cluster of differentiation 163 (CD163), human leukocyte antigen-DR (HLA-DR), and lipopolysaccharide (LPS)-stimulated levels of NF-κBp65, tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were determined in patients with AALF, chronic liver disease, and healthy controls. Immunohistochemistry and multispectral imaging of AALF explant tissue determined the cellular sources of SLPI and hepatic macrophage phenotype. The phenotype and function of monocytes and macrophages was determined following culture with recombinant human (rh)-SLPI, liver homogenates, and plasma derived from AALF patients in the presence and absence of antihuman (α)SLPI. Hepatic and circulatory concentrations of SLPI were elevated in AALF and immunohistochemistry revealed SLPI expression in biliary epithelial cells and within hepatic macrophages (h-mψ) in areas of necrosis. H-mψ and circulating monocytes in AALF exhibited an anti-inflammatory phenotype and functional characteristics; typified by reductions in NF-κBp65, TNF-α, and IL-6 and preserved IL-10 secretion following LPS challenge. Culture of healthy monocytes with AALF liver homogenates, plasma, or rhSLPI induced monocytes with strikingly similar anti-inflammatory characteristics which were reversed by inhibiting the activity of SLPI. Conclusion: SLPI is a pivotal mediator of anti-inflammatory responses in AALF through modulation of monocyte/macrophage function, which may account for the susceptibility to sepsis in AALF.

KW - LEUKOCYTE PROTEASE INHIBITOR

KW - SECRETORY LEUKOPROTEASE INHIBITOR

KW - LIPOPOLYSACCHARIDE-STIMULATED MACROPHAGES

KW - INFLAMMATORY RESPONSE

KW - PROTEINASE-INHIBITOR

KW - FAILURE

KW - EXPRESSION

KW - HEPATOTOXICITY

KW - PROLIFERATION

KW - ACTIVATION

U2 - 10.1002/hep.26933

DO - 10.1002/hep.26933

M3 - Article

SN - 0270-9139

VL - 59

SP - 1564

EP - 1576

JO - Hepatology

JF - Hepatology

IS - 4

ER -

Secretory leukocyte protease inhibitor: A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure

Abstract

Keywords

UN SDGs

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