Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2


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 options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Elevated PGE2 in plasma of patients admitted to hospital with acute decompensation is immunosuppressive.
Figure 2: Plasma from patients with ESLD but not from those with stable cirrhosis demonstrates PGE2-mediated immunosuppression.
Figure 3: Inhibiting PGE2 restores bacterial killing and survival following bacterial infection in mouse models of liver injury.
Figure 4: PGE2-mediated immunosuppression by AD plasma is improved by albumin.


  1. 1

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

    Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

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

    Article  Google Scholar 

  4. 4

    Moreau, R. 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).

    Article  Google Scholar 

  5. 5

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

    Article  Google Scholar 

  6. 6

    O'Brien, A.J., Welch, C.A., Singer, M. & Harrison, D.A. 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).

    Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

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

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

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

    Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

    Fullerton, J.N., O'Brien, A.J. & Gilroy, D.W. Pathways mediating resolution of inflammation: when enough is too much. J. Pathol. 231, 8–20 (2013).

    Article  Google Scholar 

  14. 14

    Fullerton, J.N., O'Brien, A.J. & Gilroy, D.W. Lipid mediators in immune dysfunction after severe inflammation. Trends Immunol. 35, 12–21 (2014).

    CAS  Article  Google Scholar 

  15. 15

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

    CAS  Article  Google Scholar 

  16. 16

    Bourdonnay, E., Serezani, C.H., Aronoff, D.M. & Peters-Golden, M. Regulation of alveolar macrophage p40phox: hierarchy of activating kinases and their inhibition by PGE2. J. Leukoc. Biol. 92, 219–231 (2012).

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

    Medeiros, A.I., Serezani, C.H., Lee, S.P. & Peters-Golden, M. Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling. J. Exp. Med. 206, 61–68 (2009).

    CAS  Article  Google Scholar 

  19. 19

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

    CAS  Article  Google Scholar 

  20. 20

    Yang, J., Petersen, C.E., Ha, C.E. & Bhagavan, N.V. Structural insights into human serum albumin-mediated prostaglandin catalysis. Protein Sci. 11, 538–545 (2002).

    CAS  Article  Google Scholar 

  21. 21

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

    CAS  Article  Google Scholar 

  22. 22

    Goss, J.A., Mangino, M.J. & Flye, M.W. Prostaglandin E2 production during hepatic regeneration downregulates Kupffer cell IL-6 production. Ann. Surg. 215, 553–559, discussion 559–560 (1992).

    CAS  Article  Google Scholar 

  23. 23

    McAnulty, R.J., Hernandez-Rodriguez, N.A., Mutsaers, S.E., Coker, R.K. & Laurent, G.J. Indomethacin suppresses the anti-proliferative effects of transforming growth factor-beta isoforms on fibroblast cell cultures. Biochem. J. 321, 639–643 (1997).

    CAS  Article  Google Scholar 

  24. 24

    Runyon, B.A. 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).

    Article  Google Scholar 

  25. 25

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

    Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 28

    Romanelli, R.G. 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).

    CAS  Article  Google Scholar 

  29. 29

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

    CAS  Article  Google Scholar 

  30. 30

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

    CAS  Article  Google Scholar 

Download references


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




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.

Corresponding author

Correspondence to Derek W Gilroy.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Tables 1–4 (PDF 809 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

O'Brien, A., Fullerton, J., Massey, K. et al. Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat Med 20, 518–523 (2014).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing