Secretory leukocyte protease inhibitor: A pivotal mediator... : Hepatology (original) (raw)

Liver Injury and Regeneration

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

Antoniades, Charalambos Gustav1,2; Khamri, Wafa1; Abeles, Robin D.2; Taams, Leonie S.3; Triantafyllou, Evangelos2; Possamai, Lucia A.1; Bernsmeier, Christine2; Mitry, Ragai R.2; O'Brien, Alistair4; Gilroy, Derek5; Goldin, Robert1; Heneghan, Michael2; Heaton, Nigel2; Jassem, Wayel2; Bernal, William2; Vergani, Diego2; Ma, Yun2; Quaglia, Alberto2; Wendon, Julia2; Thursz, Mark1

1_Section of Hepatology, St Mary's Hospital, Imperial College, London, UK_

2_Institute of Liver Sciences, King's College London, London, UK_

3_Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London, UK_

4_Centre for Clinical Pharmacology, Division of Medicine, Rayne Institute, University College London, UK_

5_Department of Cellular Pathology, St. Mary's Hospital, London, UK_

Received 15 August 2013; Accepted 12 November 2013

Address reprint requests to: Dr. C.G. Antoniades, Section of Hepatology, St Mary's Hospital, Imperial College, London, 10th Floor, QEQM Building, South Wharf Road London W2 1NY, UK, and Institute of Liver Sciences, King's College London, Denmark Hill Campus, Denmark Hill, London, SE5 9RS, UK. E-mail: [email protected]; Tel: +44 207 3312 6454; fax: +4420 7724 9369.

Joint first authors.

Joint senior authors.

Potential conflict of interest: Nothing to report.

Supported by the Medical Research Council (MRC) Clinician Scientist Award (to CGA); EASL Sheila Sherlock Physican Scientist Award (to CGA); Rosetrees Charitable Trust.

Additional supporting information may be found in the online version of this article:

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. (HEPATOLOGY 2014;59:1564-1576)