Letter | Published:

Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2

Nature Medicine volume 20, pages 518523 (2014) | Download Citation

Abstract

Liver disease is one of the leading causes of death worldwide1. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system2,3,4; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E2 (PGE2) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE2-dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE2-mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro. Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE2, reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus. Taken together, human albumin solution infusions may be used to reduce circulating PGE2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & The global impact of hepatic fibrosis and end-stage liver disease. Clin. Liver Dis. 12, 733–746 (2008).

  2. 2.

    & Deficient serum bactericidal activity against Escherichia coli in patients with cirrhosis of the liver. J. Clin. Invest. 63, 912–921 (1979).

  3. 3.

    et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 35, 140–148 (2002).

  4. 4.

    et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 144, 1426–1437 (2013).

  5. 5.

    et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 55, 1551–1561 (2012).

  6. 6.

    , , & Prevalence and outcome of cirrhosis patients admitted to UK intensive care: a comparison against dialysis-dependent chronic renal failure patients. Intensive Care Med. 38, 991–1000 (2012).

  7. 7.

    et al. Impaired monocyte function in liver cirrhosis. Br. Med. J. (Clin. Res. Ed.) 282, 1262–1263 (1981).

  8. 8.

    & Abnormalities of neutrophil phagocytosis, intracellular killing and metabolic activity in alcoholic cirrhosis and hepatitis. Hepatology 6, 252–262 (1986).

  9. 9.

    et al. Ammonia impairs neutrophil phagocytic function in liver disease. Hepatology 48, 1202–1212 (2008).

  10. 10.

    et al. Management of infections in cirrhotic patients: report of a consensus conference. Dig. Liver Dis. 46, 204–212 (2014).

  11. 11.

    & The anti-inflammatory effects of prostaglandins. J. Investig. Med. 57, 703–708 (2009).

  12. 12.

    Regulation of immune responses by prostaglandin E2. J. Immunol. 188, 21–28 (2012).

  13. 13.

    , & Pathways mediating resolution of inflammation: when enough is too much. J. Pathol. 231, 8–20 (2013).

  14. 14.

    , & Lipid mediators in immune dysfunction after severe inflammation. Trends Immunol. 35, 12–21 (2014).

  15. 15.

    et al. Prostaglandin E2 suppresses bacterial killing in alveolar macrophages by inhibiting NADPH oxidase. Am. J. Respir. Cell Mol. Biol. 37, 562–570 (2007).

  16. 16.

    , , & Regulation of alveolar macrophage p40phox: hierarchy of activating kinases and their inhibition by PGE2. J. Leukoc. Biol. 92, 219–231 (2012).

  17. 17.

    , & Prostaglandin E2 inhibits alveolar macrophage phagocytosis through an E-prostanoid 2 receptor-mediated increase in intracellular cyclic AMP. J. Immunol. 173, 559–565 (2004).

  18. 18.

    , , & Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling. J. Exp. Med. 206, 61–68 (2009).

  19. 19.

    & Prostaglandin E2 and the pathogenesis of pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 45, 445–452 (2011).

  20. 20.

    , , & Structural insights into human serum albumin-mediated prostaglandin catalysis. Protein Sci. 11, 538–545 (2002).

  21. 21.

    et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J. Hepatol. 42, 195–201 (2005).

  22. 22.

    , & Prostaglandin E2 production during hepatic regeneration downregulates Kupffer cell IL-6 production. Ann. Surg. 215, 553–559, discussion 559–560 (1992).

  23. 23.

    , , , & Indomethacin suppresses the anti-proliferative effects of transforming growth factor-beta isoforms on fibroblast cell cultures. Biochem. J. 321, 639–643 (1997).

  24. 24.

    Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology 57, 1651–1653 (2013).

  25. 25.

    Current indications for the use of albumin in the treatment of cirrhosis. Ann. Hepatol. 10 (suppl. 1), S15–S20 (2011).

  26. 26.

    et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 46, 831–840 (2007).

  27. 27.

    et al. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications. Hepatology 58, 1836–1846 (2013).

  28. 28.

    et al. Long-term albumin infusion improves survival in patients with cirrhosis and ascites: an unblinded randomized trial. World J. Gastroenterol. 12, 1403–1407 (2006).

  29. 29.

    et al. Characterization of time-related changes after experimental bile duct ligation. Br. J. Surg. 95, 646–656 (2008).

  30. 30.

    et al. A novel model of CCl4-induced cirrhosis with ascites in the mouse. J. Hepatol. 51, 991–999 (2009).

Download references

Acknowledgements

We thank R. Mookerjee (Royal Free Hospital) for allowing use of samples from the DASIMAR study, N. Shah for collecting these samples and N. Davies for technical assistance. We also thank A. Healey for technical support and H. Antoniades for facilitating sample acquisition. E. coli and GBS clinical isolates were provided by V. Gant, University College London Hospitals. D.W.G. is a Wellcome Trust senior research fellow and support for work presented here was provided by the Wellcome Trust. Support was also provided by a grant from the National Institute of Health Research University College London Hospitals Biomedical Research Centre (A.J.O.).

Author information

Affiliations

  1. Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK.

    • Alastair J O'Brien
    • , James N Fullerton
    • , Grace Auld
    • , Sarah James
    • , Justine Newson
    • , Effie Karra
    •  & Derek W Gilroy
  2. Manchester Pharmacy School, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

    • Karen A Massey
    •  & Anna Nicolaou
  3. Division of Medicine, University College London, London, UK.

    • Gavin Sewell
  4. Department of Histopathology, University College London Hospitals, London, UK.

    • Alison Winstanley
  5. Liver Unit, Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, London, UK.

    • William Alazawi
  6. Hospital Clínic de Barcelona, Servicio de Hepatología, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

    • Rita Garcia-Martinez
  7. Centro de Investigacion Biomédica en Red de Enfermedades Hepaticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain.

    • Joan Cordoba

Authors

  1. Search for Alastair J O'Brien in:

  2. Search for James N Fullerton in:

  3. Search for Karen A Massey in:

  4. Search for Grace Auld in:

  5. Search for Gavin Sewell in:

  6. Search for Sarah James in:

  7. Search for Justine Newson in:

  8. Search for Effie Karra in:

  9. Search for Alison Winstanley in:

  10. Search for William Alazawi in:

  11. Search for Rita Garcia-Martinez in:

  12. Search for Joan Cordoba in:

  13. Search for Anna Nicolaou in:

  14. Search for Derek W Gilroy in:

Contributions

D.W.G. and A.J.O. conceived of the idea, and A.J.O. carried out the work. D.W.G. and A.J.O. cowrote the paper, and J.N.F. edited. J.N.F., G.S., J.N., S.J., E.K. and G.A. carried out biochemical assays, and W.A. (Royal London Hospitals), J.C. and R.G.-M. (both from ALFAE and MACHT clinical trials) supplied clinical samples. K.A.M. and A.N. carried out ESI/LC-MS/MS analysis, and A.W. carried out histological analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Derek W Gilroy.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–5 and Supplementary Tables 1–4

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.3516

Further reading