Interleukin-22 in the pathogenesis and potential treatment of liver diseases☆

Shi Yin,Dechun Feng

aDepartment of Geriatrics,Af fi liated Provincial Hospital of Anhui Medical University,Hefei,China

bLaboratory of Liver Diseases,National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health,Bethesda,MD,USA

1.Introduction

Interleukin(IL)-22 is a member of the IL-10 family of cytokines that is produced by many immune cell types,such as helper T(Th)17,Th22,natural killer(NK)cells and natural killer T(NKT)cells.1,2IL-22 binds to a heterodimeric receptor(R)complex composed of IL-10R2 and IL-22R1.IL-10R2 is ubiquitously expressed while IL-22R1 expression is restricted mainly to epithelial cells,but not on cells of hematopoietic origin.3,4In the liver,IL-22R1 is expressed in hepatocytes,liver progenitor cells(LPCs)and hepatic stellate cells(HSCs).5-7Only cells that express both IL-22R1 and IL-10R2 can respond to IL-22.

IL-22 binding to its receptor strongly activates signal transducer and activator of transcription(STAT)3 and promotes the expression of survival genes,such asBcl-xLandBcl2.7,8IL-22 can also activate STAT5,extracellular regulated kinase(ERK),JNK(c-Jun N-terminal kinase),and p38 mitogen-activated protein(MAP)kinase pathways.8Interestingly,IL-22 is produced by activated immune cells but protects tissues from the damage caused by various factors,including activated immune cells themselves.The protective effects of IL-22 have been observed in many tissues and organs,such as pancreas,intestine,kidney,lung and liver.7,9-12In this review,we will focus on the effects of IL-22 on liver injury,liver repair and the development of liver cancer.

2.IL-22 in liver injury caused by various factors

2.1.IL-22 and immune-mediated liver injury

The protective effects of IL-22 in hepatocytes against various immune-mediated liver injuries have been well documented.In a model of T cell-mediated liver injury that was established by injecting Tcell mitogen concanavalin A(Con A)into mice,IL-22 was produced by activated T cells and blockade of IL-22 by neutralizing antibody enhanced liver injury.7In contrast,treatment of recombinant IL-22 attenuated liver damage in this model.This finding was con firmed by several follow-up studies using mice with overexpression of IL-22 or IL-22 de ficiency.13-16These studies clearly demonstrated that overexpression of IL-22 protected the liver from attack of activated T cells,while lack of IL-22 worsened the liver damage.

Recently,the aryl hydrocarbon receptor(AhR),a ligandactivated nuclear transcription factor,was reported crucial for the production of IL-22 in the ConA-induced liver injury model.17AhR-de ficient mice produced much less IL-22 and were more susceptible to liver injury after ConA treatment.17In addition,IL-22 could not only reduce the severity of ConA-induced liver injury but also promoted repair of the damage caused by ConA treatment.18The mechanism underlying the hepatoprotective effects of IL-22 maybe attributed to the activation of STAT3 and the subsequent upregulation of anti-apoptotic genes,such asBcl-2,Bcl-xLandMcl-1.7,14,15The treatment of lipopolysaccharides(LPS)activates macrophages/Kupffer cells and causes liver damage.The treatment of IL-22 also improved acute liver failure induced byD-galactosamine(GalN)and LPS in both mouse and rat models in which the activation of macrophages/Kupffer cells was critical in liver damage.19,20In addition to anti-apoptotic genes,the expressions of antioxidant genes,such as heme oxygenase-1(HO-1)and redox factor-1(Ref-1),were also upregulated with IL-22 treatment and might be involved in the protective effects of IL-22 in the LPS/GalN-induced liver injury model.19

2.2.IL-22 in chemical and drug induced liver injury(DILI)

Since immune cells lack IL-22R,the hepatoprotective effects of IL-22 are unlikely mediated by the regulation of immune cells.This notion was supported by several studies in carbon tetrachloride(CCl4)or acetaminophen(APAP)-induced liver injury models in which the activation of immune cells only played minimal roles in the development of liver damage.Hydrodynamic gene delivery of IL-22 significantly protected against liver necrosis induced by CCl4administration.14Moreover,Scheiermannet al.21showed that IL-22 significantly reduced serum alanine aminotransferase(ALT)levels and histopathologic damage in APAP-induced liver injury,while IL-22 itself did not display any acute immunomodulation/stimulation according to the analysis of in flammatory cytokine production.Another study showed that plasma IL-22 levels were higher in DILI patients with improved liver function compared with those with unimproved liver function.22Our own study further supported the finding that pretreatment of IL-22 significantly reduced the severity of APAP-induced liver injury,and we con firmed that STAT3 is critical in the protective effects of IL-22 in this model using liverspecific STAT3 knockout mice.23However,our study also showed that long-term exposure of IL-22 maystrongly induce expression of liver cytochrome P450 enzymes Cyp2E1 and Cyp1A2.Increased Cyp2E1 and Cyp1A2 were responsible for the metabolism of APAP to the toxic reactive metabolite N-acetyl-p-benzoquinone imine and made mice more susceptible to APAP-induced liver injury.23

2.3.IL-22 in alcoholic liver injury

Excessive alcohol drinking can lead to the development of alcoholic liver diseases(ALD),which include a wide spectrum of liver disorders such as fatty liver,alcoholic hepatitis,liver fibrosis or livercirrhosis.Currently,there is no effective and specific treatment for ALD.Our previous study showed that IL-22 treatment signi ficantly improved alcoholic fatty liver,liver injury,and hepatic oxidative stress in a newly established chronic plus binge ALD model by upregulating several antioxidant,anti-apoptotic,and antimicrobial genes.24The bene ficial effects of IL-22 on ALD were supported by another study using an alcohol-induced liver injury model with seven doses of alcohol.25The conventional treatments for ALD,such as corticosteroids or tumor necrosis factor alpha(TNF-α)inhibitor therapy,usually cause an increased chance of infection since these drugs are immune suppressive.26In contrast,IL-22 only targets hepatocytes but not immune cells.Moreover,IL-22 can promote the production of antibacterial proteins such as lipocalin2 and the Reg family of antimicrobial proteins.24,27These observations suggest that IL-22 could be a novel promising strategy for treating ALD.In support of this possibility,a clinical trial for IL-22 for ALD is ongoing(ClinicalTrials.gov Identi fier:NCT02655510).

3.IL-22 in viral hepatitis

Increased levels of IL-22 were observed in hepatitis B virus(HBV)-and hepatitis C virus(HCV)-infected patients in our study as well as reports from many other groups.5,15,28-31Th17 cells,which accumulate in the liver of both HBV and HCV patients,were considered as the major source of IL-22.28,30-34However,IL-22 itself did not directly inhibit HCV replicationin vitroand HBV replicationin vivo.28,29Moreover,IL-22 does not affect the antiviral activity of interferon(IFN)-λin hepatocytes.35The role of IL-22 in HBV infection remains controversial.The hepatoprotective effects of IL-22 has been well documented in many reports,as discussed above.However,IL-22 was also considered a pro-in flammatory cytokine,as evidenced by the observation that neutralization of IL-22 significantly increased the production of chemokines and in filtration of in flammatory cells into the liver.28,34These reports might suggest that,on one hand,IL-22 promotes the recruitment of in flammatory cells into the liver to fight against virus by upregulating chemokine expression,while on the other hand,IL-22 protects hepatocytes against immune-mediated liver damage.Studies on the role of IL-22 on the pathogenesis of HCV are limited,and more investigation is needed toclarify how elevatedIL-22 regulates in flammation and liver injury in HCV patients.

4.IL-22 in liver fibrosis

Liver fibrosis is characterized by the accumulation of extracellular matrix proteins,including collagen.Liver fibrosis occurs in most types of chronic liver diseases,such as HBV or HCV infection and alcoholic and nonalcoholic steatohepatitis.Activated HSCs are considered the major collagen-producing cells,and thus most of the anti- fibrotic strategies have focused on preventing the activation of HSCs.Our group found that IL-22R1 was expressed in HSCs and IL-22 can directly activate STAT3in vitro.Importantly,our data showed that overexpression of IL-22 reduced liver fibrosis and accelerated the resolution of liver fibrosis during recovery in a chronic CCl4-induced liver fibrosis model.The mechanism study indicated that IL-22 increased the number of senescent HSCs.Further studies have suggested that IL-22 can induce senescence in activated HSCs by activating the p53-p21 pathway in a STAT3-dependentmanner.6Theanti- fibroticeffectsofIL-22 were con firmed by several studies from other groups.36-40Menget al.37showed that IL-22 knockout mice were more susceptible to CCl4-induced liver fibrosis,while treatment with IL-22 protected mice from liver fibrosis in bile duct ligation-induced liver fibrosis.Human studies revealed an inverse correlation between fibrosis stage and IL-22 expression in chronic HBV-infected liver samples.31Similarly,in HCV patients,high IL-22 levels in peripheral blood mononuclear cells correlated with protection against hepatic fibrosis and portal hypertension.38Another report in a HBV transgenic mouse model showed that IL-22 may stimulate HSCs to produce chemokines and recruit Th17 cells to the liver to promote liver fibrosis.34However,the pro- fibrotic effects of IL-22 in this study were indirect and occurred in the advanced stage of liver fibrosis.

5.IL-22 in liver cancer and liver progenitor cells

As a strong activator of STAT3,which is a well-established oncogenic transcription factor in liver cancer,41the effects of IL-22 on liver cancer is the major concern for using IL-22 to treat liver injury for patients.IL-22 was significantly upregulated in tumor in filtrated leukocytes of hepatocellular carcinoma(HCC)patients,and excessive IL-22 promoted tumor growth and metastasis by activating STAT3.42Serum IL-22 levels were considered as a negative prognostic indicator in HCC patients.43In addition,Th22 cells were associated with HCC development,44,45while inhibition of IL-22 by metformin suppressed tumor growth in a mouse HCC model.46Our group also found that IL-22 can promote HCC cell growth.7We also recently reported that IL-22 transgenic mice developed more and larger liver tumors in a diethylnitrosamine-induced liver cancer model.15Interestingly,mice with IL-22 overexpression did not spontaneously develop liver tumors.15These findings suggest that IL-22 alone does not initiate liver tumors,but can promote hepatic carcinogenesis together with other risk factors.

We also demonstrated that IL-22 can promote the growth of LPCs,which partiallyexplains the expansion of LPCs in chronic viral hepatitis patients resulting from higher IL-22 levels in these patients.5The expansion of LPCs by IL-22 did not contribute to HCC but may be helpful for liver repair after chronic liver injury.HCC does not usually originate from normal LPCs,47however,additional factors such as viral infection are necessary for the transformation of LPCs to lung cancer stem cells and the subsequent HCC initialization.48

6.IL-22 in liver regeneration

IL-22 can directly promote human primary hepatocyte proliferationin vitro.49This effect was con firmedin vivousing a partial hepatectomy model,in which the IL-22 blocking antibody signi ficantly impaired liver regeneration after partial hepatectomy.50Our IL-22 transgenic mice also showed accelerated liver regeneration after partial hepatectomy.15Similar results were also found in liver regeneration in the ConA-induced liver injury model.18Raoet al.51found that γδT cells were recruited into the liver after injury and promoted liver regeneration by secreting IL-17 and IL-22 in the partial hepatectomy model.This conclusion was further supported by a study that showed that innate immune cell-derived IL-22 was required for ef ficient liver regeneration.52In a human study,a positive correlation between intrahepatic IL-22 level and liver regeneration was found in DILI patients.22

7.IL-22 in metabolism

Several studies have examined the effects of IL-22 on metabolism,especially in lipid and glucose metabolism in the liver.Yanget al.53found that IL-22 treatment suppressed lipogenesis-related genes,including several genes encoding critical transcription factors and enzymes in the liver.Liver steatosis was significantly reduced by IL-22 treatment in wild-type mice that were fed a highfat diet and in leptin-de ficientob/obmice.Our results showed that only mice with very high serum levels of IL-22(4000-7000 pg/ml)were resistant to fatty liver.One of the IL-22 transgenic strains with～600 pg/ml serum IL-22 levels developed liver steatosis and insulin resistance that was comparable with that of wild-type mice.However,we found that a single dose of IL-22 downregulated the hepatic expression of gluconeogenic genes and subsequently inhibited hepatic gluconeogenesis.54

8.Summary

The production of IL-22 in immune cells is tightly controlled by several transcription factors.Among them,AhR is the most important regulator in the production of IL-22.55CD4+T cells without AHR expression show reduced levels of IL-22,and AHR ligands increase IL-22 expression.Several other transcription factors,such as Hypoxia-inducible factor(HIF)-1α,56RORγt and basic leucine zipper activating transcription factor-like(BATF),57,58may enhance IL-22 production,while Foxp3 and c-Maf inhibit IL-22 production.59,60As summarized in Fig.1,IL-22 shows potent effects in protecting the liver from injury caused by various reasons,such as immune cell activation,drug overdose,and excessive alcohol intake.In addition,IL-22 exhibits bene ficial effects in liver diseases by promoting liver regeneration, fibrosis resolution and antimicrobial protein production.These features indicate IL-22 as a promising drug candidate for treating liver diseases.

Fig.1.Schematic diagram of the effects of IL-22 on different cells in the liver and the role of IL-22 in liver in flammation,liver injury and liver repair.

Authors'contributions

D.Feng and S.Yin wrote the manuscript.

Con flict of interest

The authors declare that they have no con flict of interest.

Acknowledgements

This work was in supported by the National Natural Science Foundation of China(grant number:81100311,81470879/H0318 to S.Yin)and intramural program of USA National Institute on Alcohol Abuse and Alcoholism(NIAAA),National Institutes of Health(NIH).

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