Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2013 Mar 1.
Published in final edited form as: J Gastroenterol Hepatol. 2012 Mar;27(Suppl 2):89–93. doi: 10.1111/j.1440-1746.2011.07003.x

Hepatoprotective and anti-inflammatory cytokines in alcoholic liver disease

Bin Gao 1
PMCID: PMC3281557  NIHMSID: NIHMS340263  PMID: 22320924

Abstract

The activation of innate immunity by various factors (e.g., lipopolysaccharide and complements) plays an important role in initiating and promoting alcoholic liver injury via the stimulation of Kupffer cells to induce oxidative stress and to produce pro-inflammatory cytokines (e.g., tumor necrosis factor [TNF]-α) that cause hepatocellular damage. Accumulating evidence suggests that the activation of innate immunity also stimulates Kupffer cells to produce the hepatoprotective cytokine interleukin-6 (IL-6) and the anti-inflammatory cytokine IL-10 during alcoholic liver injury. IL-6 protects against alcoholic liver injury via the activation of signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via the activation of STAT3 in Kupffer cells/macrophages and the subsequent inhibition of liver inflammation. Recent studies have suggested that IL-10 may play a dual role in controlling ethanol-induced steatosis and liver injury via the inhibition of the pro-inflammatory cytokine TNF-α, thereby ameliorating alcoholic liver injury, or via the inhibition of the hepatoprotective cytokine IL-6, thereby potentiating alcoholic liver injury. IL-22 is another important hepatoprotective cytokine that protects against acute and chronic alcoholic liver injury by binding to a complex composed of IL-10R2 and IL-22R receptor chains on the surfaces of hepatocytes. Finally, IL-22 treatment is a potential therapeutic option for treating severe forms of alcoholic liver disease because of its antioxidant, antiapoptotic, antisteatotic, proliferative, and antimicrobial effects, as well as the potential added benefit of few side effects.

Keywords: IL-6, IL-10, IL-22, alcoholic liver disease

Introduction

Chronic alcohol consumption is a leading cause of chronic liver disease in developed countries and is becoming the leading cause of this disease in developing countries. 1, 2 The National Institute on Alcohol Abuse and Alcoholism recently released its latest surveillance report showing that 48% of the cirrhosis cases in the USA in 2007 were alcohol-related.1 Early studies indicated that ethanol metabolism-associated oxidative stress, glutathione depletion, abnormal methionine metabolism, and malnutrition contribute to the pathogenesis of alcoholic liver disease (ALD).3–6 The research findings from the last two decades have suggested that the activation of innate immunity by various factors (e.g., lipopolysaccharide [LPS], complement, and tumor necrosis factor [TNF]-α) also plays an important role in initiating and promoting ALD.7–10 It is believed that chronic alcohol consumption results in the activation of innate immunity followed by the production of pro-inflammatory cytokines, such as TNF-α, and the subsequent induction of hepatocellular damage. 7–10 In addition to the production of pro-inflammatory cytokines, the activation of innate immunity upregulates hepatoprotective cytokines (e.g., interleukin-6 [IL-6]) and anti-inflammatory cytokines (e.g., IL-10 and adiponectin) in ALD. 11, 12 Recent studies from our laboratory have suggested that both IL-6 and IL-10 play compensatory roles in protecting against alcoholic liver injury and inflammation, respectively; the results of these studies are summarized in this review. In addition, our recent research suggests that another hepatoprotective cytokine, IL-22, may have a therapeutic potential in treating severe forms of ALD.

Hepatoprotective (IL-6 and IL-22) and anti-inflammatory cytokine (IL-10): the activation of signal transducer and activator of transcription 3 (STAT3) in the liver

Although IL-6, IL-10, and IL-22 activate (via STAT3) similar signaling pathways in the liver, they target different types of liver cells (Fig. 1).13 For example, IL-6R and its signal-transducing chain, gp130, are ubiquitously expressed on all types of liver cells, including hepatocytes, Kupffer cells, hepatic stellate cells, and sinusoidal endothelial cells, all of which respond to IL-6 stimulation. Upon binding to IL-6R on hepatocytes, IL-6 induces gp130 dimerization and the subsequent dimerization of gp130-associated Janus kinases (JAKs), which leads to JAK phosphorylation, followed by STAT3 activation. The activated STAT3 forms a dimer, translocates into the nucleus, and upregulates the expression of a variety of genes that play important roles in protecting against liver injury and promoting liver regeneration.13 The activation of STAT3 by IL-6 in sinusoidal endothelial cells may also contribute to the hepatoprotective function of IL-6.14, 15 In addition, IL-6 may regulate liver fibrosis and inflammation via the activation of STAT3 in hepatic stellate cells and Kupffer cells, respectively. However, the evidence for this role of IL-6 remains inconclusive. In addition, many other IL-6 family cytokines activate STAT3 in hepatocytes and likely play roles similar to those of IL-6 in protecting against hepatocellular damage and promoting liver regeneration.13

Fig. 1. IL-6-, IL-22-, and IL-10-induced activation of STAT3 in the liver.

Fig. 1

Open in a new tab

In hepatocytes, both IL-6 and IL-22 induce STAT3 activation and play important roles in hepatoprotection and liver regeneration. In Kupffer cells, IL-6 induces transient STAT3 activation and contributes to the pro-inflammatory response, whereas IL-10 induces prolonged STAT3 activation and contributes to the anti-inflammatory response. In sinusoidal endothelial cells, IL-6 induces STAT3 activation and subsequently promotes cell survival. In hepatic stellate cells, IL-6 induces STAT3 activation; however, the roles of STAT3 in stellate cell activation and fibrogenesis remain obscure.

IL-22 exerts its functions via interactions with IL-10R2 and IL-22R on cell surface, the former of which is ubiquitously expressed on all types of liver cells, whereas the latter is expressed primarily on epithelial cells, such as hepatocytes.16 Thus, IL-22 only targets hepatocytes that express both IL-10R2 and IL-22R, and plays important roles in hepatoprotection and liver regeneration.17–20 The IL-10 homodimer signals through a receptor complex composed of two chains of IL-10R2 and two of IL-10R1. Because IL-10R1 is only expressed in immune cells, thus IL-10 only targets immune cells, including Kupffer cells, in the liver and acts as a key anti-inflammatory cytokine in controlling liver inflammation.

The interplay of the hepatoprotective (IL-6) and anti-inflammatory cytokine (IL-10) in controlling alcoholic liver injury

Serum and hepatic IL-6 levels are elevated in patients with ALD 21 and in animal models of alcoholic liver injury.22 Although the serum levels of IL-6 positively correlate with the disease severity in ALD patients,21 studies using animal models have suggested that IL-6 plays an important role in protecting against alcoholic liver injury. In a mouse model of alcoholic liver injury, IL-6-deficient mice are more susceptible to ethanol-induced hepatic steatosis, apoptosis, and mitochondrial DNA damage than are wild-type animals.23–25 In vivo treatment with IL-6 ameliorates ethanol-induced liver injury in mice,26 and ex vivo treatment with IL-6 prevents fatty liver transplant failure in rats.15 Here, I propose a model depicting the hepatoprotective role of IL-6 in alcoholic liver injury (Fig. 2).

Fig. 2. Elevations of IL-6 and IL-10 are part of a host defense strategy to repair the injured liver and control inflammation in ALD.

Fig. 2

Open in a new tab

Chronic alcohol consumption leads to innate immunity activation via various factors (e.g., LPS, TNF-α, and complement), with subsequent hepatocellular damage. The activation of innate immunity also promotes the production of the hepatoprotective cytokine IL-6, which plays an important compensatory role in repairing liver damage via the activation of STAT3 and the upregulation of multiple hepatoprotective genes in hepatocytes. The activation of innate immunity also produces the anti-inflammatory cytokine IL-10, which activates STAT3 in Kupffer cells/macrophages and controls liver inflammation. However, IL-10 plays a dual role in controlling alcoholic fatty liver and liver injury: first, IL-10 inhibits LPS, TNF-α, and complement activation, thereby reducing steatosis and liver damage; second, IL-10 blocks IL-6 production, thereby reducing liver regeneration and enhancing steatosis and liver damage.

In this model, chronic alcohol consumption results in an elevation of LPS levels in the liver via either the promotion of bacterial overgrowth 27 or an augmentation of gut permeability and the translocation of bacterial-derived LPS from the gut to the liver.9 Elevated LPS stimulates Kupffer cells/macrophages to induce oxidative stress and to produce pro-inflammatory cytokines that cause hepatocellular damage. Chronic alcohol consumption also causes complement activation, followed by the induction of TNF-α and liver damage.28, 29 However, LPS and complement activation also stimulate Kupffer cells to produce IL-6. The elevated IL-6 then stimulates STAT3 activation in hepatocytes and subsequently upregulates the expression of anti-apoptotic genes (e.g., Bcl-2 and BcI-xL), anti-oxidative genes (e.g., metallothioneins 1 and 2), and mitochondrial DNA repair genes (e.g., OGG-1 and Neil 1)23, 24 and downregulates the expression of lipogenic genes (e.g., SREBP-1c).22 Thus, elevated IL-6 plays a key role in repairing ethanol-induced hepatocellular damage by ameliorating steatosis, preventing hepatocellular damage, and promoting liver regeneration. Consistent with these findings, the hepatocyte-specific deletion of STAT3, a key IL-6 downstream signal, has been shown to exacerbate ethanol-induced steatosis and liver injury.22 At present, whether the activation of STAT3 is responsible for the IL-6-induced upregulation of the hepatoprotective genes discussed above remains obscure.

IL-10 is a well-documented anti-inflammatory cytokine, and as expected, IL-10-deficient mice exhibit increased liver inflammation after being fed ethanol or a high-fat diet.30 However, surprisingly, IL-10-deficient mice have less steatosis and lower levels of serum ALT after being fed these diets compared with wild-type mice.30 Moreover, IL-10-deficient mice display elevated hepatic and serum IL-6 levels and hepatic STAT3 activation after being fed ethanol or a high-fat diet. An additional deletion of IL-6 or hepatocyte STAT3 restores hepatic steatosis and the elevation of serum ALT in IL-10-deficient mice, suggesting that the elevation of inflammation-associated hepatic IL-6 and STAT3 activation contributes to the reduced steatosis and serum ALT in IL-10-deficient mice.30 In addition, IL-10-deficient mice display increased liver regeneration after partial hepatectomy.31 This increased regeneration is due, at least in part, to elevated hepatic IL-6 and STAT3 activation because the additional deletion of IL-6 or hepatic STAT3 reduces liver regeneration in IL-10-deficient mice.31

In summary, as shown in Fig. 2, IL-10 inhibits innate immunity activation (e.g., LPS and TNF-α),11 thereby ameliorating steatosis and liver injury, and it inhibits hepatoprotective cytokines, such as IL-6,30 thereby promoting steatosis and inhibiting liver regeneration. Thus, the overall effect of IL-10 on hepatic steatosis and liver injury is likely determined by the balance between pro-inflammatory cytokines that promote steatosis and liver injury and hepatoprotective cytokines that prevent steatosis and promote liver regeneration.

The therapeutic potential of the hepatoprotective cytokine IL-22 in treating severe forms of ALD

Although the hepatoprotective effect of IL-6 on alcoholic liver injury is well documented, 23–25 and in vivo IL-6 treatment ameliorates fatty liver in rodent models,26 the therapeutic application of IL-6 in the treatment of patients with ALD is limited by the many potential side effects of IL-6, which likely result from the ubiquitous expression of IL-6R and its signal-transducing chain gp130, as well as the existence of soluble IL-6R in the serum. Although in vivo treatments with IL-6 are impractical, a simple in vitro treatment of donor fatty liver with IL-6 may render marginal fatty livers usable for clinical transplantation.15 Recent studies from our group have suggested that IL-22, another hepatoprotective cytokine, may have a therapeutic potential to treat severe forms of ALD.

IL-22 was originally described as an IL-10-related T-cell-derived inducible factor (IL-TIF) belonging to the IL-10 family of cytokines.32 In 2004, we demonstrated for the first time that IL-22 is a critical survival factor for hepatocytes and plays a key role in protecting against Con A-induced T cell hepatitis.17 The protective role of IL-22 in T cell hepatitis was further confirmed using IL-22-deficient mice19 and IL-22 transgenic mice.18 In addition, IL-22 ameliorates steatosis and hepatocellular damage in many other models of liver injury, including high fat diet-induced fatty liver33 and acute and chronic alcoholic liver injury.34, 35 The hepatoprotective effect of IL-22 in alcoholic liver injury is likely mediated via the activation of STAT3, followed by the upregulation of anti-apoptotic genes (e.g., Bcl-2 and BcI-xL), anti-oxidative genes (e.g., metallothioneins 1 and 2), and the downregulation of lipogenic genes (e.g., SREBP-1c) in hepatocytes.35

In contrast to IL-6R, which is ubiquitously expressed, IL-22R expression is restricted to epithelial cells, including hepatocytes.16 Thus, treatment of alcoholic hepatitis with IL-22 in combination with corticosteroids or TNF-α inhibitors may have minimal side effects. Corticosteroids have been widely used, and TNF-α inhibitors have been tested in the treatment of severe forms of alcoholic hepatitis; however, the results of these studies are controversial.36–40 Both steroids and TNF-α inhibitors can block inflammation, but they also reduce liver regeneration and increase the rate of bacterial infection;37–39 the last two events may be responsible for the poor outcomes associated with these treatments. Co-treatment with IL-22 may diminish corticosteroid- or TNF-α inhibitor-induced bacterial infection and may prevent the inhibition of liver regeneration because IL-22 has an antimicrobial effect 41 and promotes liver regeneration.18, 20 Conversely, co-treatment with corticosteroids may prevent the potential pro-inflammatory effect of IL-22 treatment in the liver.42, 43 Liver-specific IL-22 transgenic mice do not display obvious liver inflammation or chemokine upregulation,18 which suggests that IL-22 treatment may have little effect on liver inflammation. Furthermore, IL-22 is not elevated in the livers of alcoholic hepatitis patients, whereas the expression of IL-22R1 is upregulated,35 which suggests that these patients may be sensitive to IL-22 treatment because of low levels of endogenous IL-22 and elevated levels of IL-22R1 in the liver.

Finally, IL-22 has been shown to promote liver tumor cell growth in vitro and ex vivo.17 Elevated levels of IL-22 are found in patients with hepatocellular carcinoma, and IL-22 has been implicated in hepatocellular carcinoma growth.44 Recently, we demonstrated that mice overexpressing IL-22 in the liver do not spontaneously develop liver tumors, but they are more susceptible to diethylnitrosamine-induced liver cancer.18 These results suggest that high levels of IL-22 alone may not initiate liver tumor development, but IL-22 may accelerate hepatic carcinogenesis via the promotion of cell survival and proliferation in existing liver tumors. Thus, the application of IL-22 should be safe for the treatment of alcoholic hepatitis patients without cirrhosis and without liver cancer, but it should not be used in patients with pre-cancerous cirrhosis or liver cancer.

Conclusions

The activation of innate immunity by various factors (e.g., LPS, Kupffer cells, and complement) results in the production of pro-inflammatory cytokines, including TNF-α, and contributes to the development and progression of ALD; 7–10 recent findings from our laboratory have suggested that the activation of these innate immunity components also plays a significant role in alleviating hepatocellular damage and promoting liver regeneration via the production of the hepatoprotective cytokine IL-6 and the anti-inflammatory cytokine IL-10. The elevation of IL-6 and IL-10 levels in ALD patients could be part of a host defense strategy to repair the damaged liver and control inflammation, respectively. Interestingly, IL-10 inhibits pro-inflammatory cytokines, such as TNF-α, thereby ameliorating ALD, and it inhibits hepatoprotective cytokines, such as IL-6, thereby potentiating ALD and reducing liver regeneration. Thus, IL-10 likely plays a dual role in controlling the progression of ALD.

Although the hepatoprotective role of IL-6 is well documented, the clinical application of IL-6 in treating ALD is limited because of its numerous potential side effects. In contrast, IL-22, another important hepatoprotective cytokine, may have greater therapeutic potential in treating severe forms of ALD because of its well-documented hepatoprotective and antimicrobial functions, as well as its potentially minimal adverse side effects due to its restricted IL-22R expression in epithelial cells. Clinical trials examining combination therapy with IL-22 plus corticosteroids or plus TNF-α inhibitors for the treatment of patients with severe alcoholic hepatitis are warranted.

Acknowledgments

This work was supported by the Intramural Program of NIAAA, NIH.

Abbreviations

ALD

alcoholic liver disease

IL

interleukin

LPS

lipopolysaccharide

JAK

Janus kinases

STAT3

signal transducer and activator of transcription 3

Footnotes

Conflict of interest

No conflicts of interest has been declared by the author.

References

  • 1.Yoon Y, Yi H. Liver cirrhosis mortality in the United States, 1970–2007 Surveillance report #88. NIAAA Homepage. 2010 http://pubs.niaaa.nih.gov/publications/surveillance88/cirr07.htm.
  • 2.Liangpunsakul S. Clinical characteristics and mortality of hospitalized alcoholic hepatitis patients in the United States. J Clin Gastroenterol. 2011;45:714–9. doi: 10.1097/MCG.0b013e3181fdef1d. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011;141:1572–85. doi: 10.1053/j.gastro.2011.09.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Hepatology. 2010;51:307–28. doi: 10.1002/hep.23258. [DOI] [PubMed] [Google Scholar]
  • 5.Tsukamoto H, Lu SC. Current concepts in the pathogenesis of alcoholic liver injury. Faseb J. 2001;15:1335–49. doi: 10.1096/fj.00-0650rev. [DOI] [PubMed] [Google Scholar]
  • 6.Hoek JB, Cahill A, Pastorino JG. Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology. 2002;122:2049–63. doi: 10.1053/gast.2002.33613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Nagy LE. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Exp Biol Med (Maywood) 2003;228:882–90. doi: 10.1177/153537020322800803. [DOI] [PubMed] [Google Scholar]
  • 8.Gao B, Seki E, Brenner DA, et al. Innate immunity in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol. 2011;300:G516–25. doi: 10.1152/ajpgi.00537.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology. 2009;50:638–44. doi: 10.1002/hep.23009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Szabo G, Mandrekar P, Petrasek J, et al. The unfolding web of innate immune dysregulation in alcoholic liver injury. Alcohol Clin Exp Res. 2011;35:782–6. doi: 10.1111/j.1530-0277.2010.01398.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Mandal P, Park PH, McMullen MR, et al. The anti-inflammatory effects of adiponectin are mediated via a heme oxygenase-1-dependent pathway in rat Kupffer cells. Hepatology. 2010;51:1420–9. doi: 10.1002/hep.23427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Petrasek J, Dolganiuc A, Csak T, et al. Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells. Hepatology. 2011;53:649–60. doi: 10.1002/hep.24059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Wang H, Lafdil F, Kong X, et al. Signal transducer and activator of transcription 3 in liverdiseases: a novel therapeutic target. Int J Bio l Sci. 2011;7:536–50. doi: 10.7150/ijbs.7.536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Miller AM, Wang H, Park O, et al. Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury. Alcohol Clin Exp Res. 2010;34:719–25. doi: 10.1111/j.1530-0277.2009.01141.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Sun Z, Klein AS, Radaeva S, et al. In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats. Gastroenterology. 2003;125:202–15. doi: 10.1016/s0016-5085(03)00696-6. [DOI] [PubMed] [Google Scholar]
  • 16.Wolk K, Witte E, Witte K, et al. Biology of interleukin-22. Semin Immunopathol. 2010;32:17–31. doi: 10.1007/s00281-009-0188-x. [DOI] [PubMed] [Google Scholar]
  • 17.Radaeva S, Sun R, Pan HN, et al. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology. 2004;39:1332–42. doi: 10.1002/hep.20184. [DOI] [PubMed] [Google Scholar]
  • 18.Park O, Wang H, Weng H, et al. In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology. 2011;54:252–61. doi: 10.1002/hep.24339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Zenewicz LA, Yancopoulos GD, Valenzuela DM, et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity. 2007;27:647–59. doi: 10.1016/j.immuni.2007.07.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Ren X, Hu B, Colletti LM. IL-22 is involved in liver regeneration after hepatectomy. Am J Physiol Gastrointest Liver Physiol. 2010;298:G74–80. doi: 10.1152/ajpgi.00075.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Hill DB, Marsano L, Cohen D, et al. Increased plasma interleukin-6 concentrations in alcoholic hepatitis. J Lab Clin Med. 1992;119:547–52. [PubMed] [Google Scholar]
  • 22.Horiguchi N, Wang L, Mukhopadhyay P, et al. Cell type-dependent pro-and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury. Gastroenterology. 2008;134:1148–58. doi: 10.1053/j.gastro.2008.01.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Hong F, Kim WH, Tian Z, et al. Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-x(L) proteins. Oncogene. 2002;21:32–43. doi: 10.1038/sj.onc.1205016. [DOI] [PubMed] [Google Scholar]
  • 24.Zhang X, Tachibana S, Wang H, et al. Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice. Hepatology. 2010;52:2137–47. doi: 10.1002/hep.23909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.El-Assal O, Hong F, Kim WH, et al. IL-6-deficient mice are susceptible to ethanol-induced hepatic steatosis: IL-6 protects against ethanol-induced oxidative stress and mitochondrial permeability transition in the liver. Cell Mol Immunol. 2004;1:205–11. [PubMed] [Google Scholar]
  • 26.Hong F, Radaeva S, Pan HN, et al. Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver disease. Hepatology. 2004;40:933–41. doi: 10.1002/hep.20400. [DOI] [PubMed] [Google Scholar]
  • 27.Yan AW, Fouts DE, Brandl J, et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology. 2011;53:96–105. doi: 10.1002/hep.24018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Cohen JI, Roychowdhury S, McMullen MR, et al. Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice. Gastroenterology. 2010;139:664–74. doi: 10.1053/j.gastro.2010.04.041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Roychowdhury S, McMullen MR, Pritchard MT, et al. An early complement-dependent and TLR-4-independent phase in the pathogenesis of ethanol-induced liver injury in mice. Hepatology. 2009;49:1326–34. doi: 10.1002/hep.22776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Miller A, Wanf H, Bertola A, et al. Inflammation-associated IL-6/STAT3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in IL-10 deficient mice. Hepatology. 2011;51:846–856. doi: 10.1002/hep.24517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Yin S, Wang H, Park O, et al. Enhanced Liver Regeneration in IL-10-Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3. Am J Pathol. 2011;178:1614–21. doi: 10.1016/j.ajpath.2011.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Dumoutier L, Louahed J, Renauld JC. Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J Immunol. 2000;164:1814–9. doi: 10.4049/jimmunol.164.4.1814. [DOI] [PubMed] [Google Scholar]
  • 33.Yang L, Zhang Y, Wang L, et al. Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22. J Hepatol. 2010;53:339–47. doi: 10.1016/j.jhep.2010.03.004. [DOI] [PubMed] [Google Scholar]
  • 34.Xing WW, Zou MJ, Liu S, et al. Interleukin-22 protects against acute alcohol-induced hepatotoxicity in mice. Biosci Biotechnol Biochem. 2011;75:1290–4. doi: 10.1271/bbb.110061. [DOI] [PubMed] [Google Scholar]
  • 35.Ki SH, Park O, Zheng M, et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology. 2010;52:1291–300. doi: 10.1002/hep.23837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360:2758–69. doi: 10.1056/NEJMra0805786. [DOI] [PubMed] [Google Scholar]
  • 37.Boetticher NC, Peine CJ, Kwo P, et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology. 2008;135:1953–60. doi: 10.1053/j.gastro.2008.08.057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Louvet A, Wartel F, Castel H, et al. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology. 2009;137:541–8. doi: 10.1053/j.gastro.2009.04.062. [DOI] [PubMed] [Google Scholar]
  • 39.Naveau S, Chollet-Martin S, Dharancy S, et al. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology. 2004;39:1390–7. doi: 10.1002/hep.20206. [DOI] [PubMed] [Google Scholar]
  • 40.Tilg H, Day CP. Management strategies in alcoholic liver disease. Nat Clin Pract Gastroenterol Hepatol. 2007;4:24–34. doi: 10.1038/ncpgasthep0683. [DOI] [PubMed] [Google Scholar]
  • 41.Aujla SJ, Kolls JK. IL-22: a critical mediator in mucosal host defense. J Mol Med. 2009;87:451–4. doi: 10.1007/s00109-009-0448-1. [DOI] [PubMed] [Google Scholar]
  • 42.Zhang Y, Cobleigh M, Lian J, et al. A Proinflammatory Role for Interleukin-22 in the Immune Response to Hepatitis B Virus. Gastroenterology. 2011;141:1897–906. doi: 10.1053/j.gastro.2011.06.051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Liang SC, Nickerson-Nutter C, Pittman DD, et al. IL-22 induces an acute-phase response. J Immunol. 2010;185:5531–8. doi: 10.4049/jimmunol.0904091. [DOI] [PubMed] [Google Scholar]
  • 44.Jiang R, Tan Z, Deng L, et al. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology. 2011;54:900–909. doi: 10.1002/hep.24486. [DOI] [PubMed] [Google Scholar]

RESOURCES