Joint first authors.
Secretory leukocyte protease inhibitor: A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure
Article first published online: 28 FEB 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 4, pages 1564–1576, April 2014
How to Cite
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. and Thursz, M. (2014), Secretory leukocyte protease inhibitor: A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure. Hepatology, 59: 1564–1576. doi: 10.1002/hep.26933
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.
- Issue published online: 24 MAR 2014
- Article first published online: 28 FEB 2014
- Accepted manuscript online: 27 NOV 2013 04:17AM EST
- Manuscript Accepted: 12 NOV 2013
- Manuscript Received: 15 AUG 2013
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)