Alcohol-induced Modulation of Signaling Pathways in Liver Parenchymal and Nonparenchymal Cells: Implications for Immunity

• ABSTRACT
• ETHANOL AND PATHWAYS OF LIPID ACCUMULATION IN THE HEPATOCYTE
• Peroxisome Proliferator-Activated Receptors (PPAR) and Steatosis
• Osteopontin and PPARα
• Adiponectin and PPARα
• Plasminogen Activator Inhibitor-1
• Oxidant Stress and Lipid Accumulation
• Other Pathways and Hepatic Lipid Accumulation
• Complement
• ETHANOL AND THE TLR4-INNATE IMMUNE SIGNALING AXIS IN KUPFFER CELLS
• Toll-like Receptor Signaling Pathways
• The Nuclear Factor Kappa B
• Cyclic AMP
• MAPK
• Nuclear Factor/Erythroid Related Factor 2
• Macrophage Iron
• ETHANOL AND IMMUNITY
• Ethanol Abuse and Antiviral Immunity
• Ethanol Abuse and Antiviral Response in Tissues Other than Liver
• ALCOHOL AND AUTOIMMUNE HOST RESPONSE
• SUMMARY AND CONCLUSIONS
• i ACKNOWLEDGEMENTS
• ABBREVIATIONS
• REFERENCES

ABSTRACT

Alcoholic liver injury involves a complex array of derangements in cellular signaling of hepatic parenchymal and nonparenchymal cells as well as cells of the immune system. In the hepatocyte, chronic ethanol abuse leads to lipid accumulation and liver steatosis. Multiple pathways are affected to promote lipid accumulation in the ethanol-exposed hepatocyte. Chronic ethanol renders Kupffer cells hyperresponsive to endotoxin, which results in production of inflammatory cytokines and the tumor necrosis factor-α via a toll-like receptor 4 dependent pathway, leading to inflammation and hepatic necrosis. Dysfunction of the innate and adaptive immune responses caused by ethanol contributes to impaired antiviral response, inflammatory injury, and autoimmune activation. Recent developments in the literature are reviewed in a model that suggests lipid accumulation, dysregulation of immunity, and impaired antiviral and autoimmune responses as three distinct, though interwoven, pathophysiological mechanisms of alcoholic liver injury.

Alcoholic liver disease (ALD) can be broadly described as varying degrees of impairment of hepatic function following chronic and excessive ethanol consumption. The pathophysiological changes in ALD are provoked by complex effects of ethanol on all cell types within the liver, affecting metabolic, immunologic, and inflammatory processes. Within the effects of alcohol, a few broad trends emerge. First, chronic ethanol (CE) consumption diverts metabolic pathways in the hepatocyte toward the accumulation of intracellular lipid in the form of triglycerides.[1] Recent investigation reveals that this accumulation of lipid is unlikely to be an effect of ethanol alone on the hepatocyte, but rather a complex interplay of ethanol-induced alterations in the cellular redox state, the transcription of lipogenic and antilipolytic factors, and cellular signaling from other cell types and distant tissues. Second, ALD involves activation of the signaling axis of the innate immune pathway, which can be characterized by a hepatic inflammatory response to gut-derived endotoxin, chiefly orchestrated by the Kupffer cell (KC), the resident macrophage of the liver. The main output of this inflammatory response is the production of tumor necrosis factor-α (TNFα) and other proinflammatory cytokines, which, in turn, are major determinants and causative agents of subsequent liver damage. Third, prolonged inflammation and hepatocyte damage appear to give rise to several other cellular and immune events that provoke further deterioration of hepatic function, including effects that span a range from impaired antiviral response, fibrotic change, and autoimmune attack. Thus, for purposes of this review, we will adopt a three-part description of signaling pathways in ALD, one that summarizes pathways leading to lipid accumulation, the endotoxin/innate immune signaling axis, and other cellular and immune events as three distinct, though overlapping, themes in the biological narrative of liver injury as a consequence of prolonged ethanol exposure.

ETHANOL AND PATHWAYS OF LIPID ACCUMULATION IN THE HEPATOCYTE

Ethanol exerts effects on the hepatocyte that divert metabolic pathways to favor the accumulation of intracellular lipid (Fig. [1]). This correlates with the earliest histopathological alterations detectable in murine models of acute ethanol or CE consumption, and the clinical observation that virtually all individuals who chronically consume ethanol develop steatosis.[2] In vitro work using precision-cut thin slices of liver tissue have demonstrated lipid accumulation within 48 hours of ethanol exposure.[3] Ethanol directly affects the activity of several nuclear receptors that exert transcriptional control on lipid metabolism, including the peroxisome proliferator-activated receptors α and gamma (PPARα and PPARγ), the sterol regulatory element binding protein-1 (SREBP1), the retinoid X receptor/liver X receptor (RXR and LXR), and other associated regulators and cofactors.

Peroxisome Proliferator-Activated Receptors (PPAR) and Steatosis

The peroxisome proliferator-activated-receptors (PPAR) are a family of proteins that act as nuclear receptors and exert transcriptional effects on pathways of lipid metabolism. Natural PPAR ligands include various lipid-derived biomolecules, including eicosanoids, leukotrienes, prostaglandins, and free fatty acids.[4] PPARα may be pharmacologically activated by drugs of the fibrate class, whereas PPARγ may be activated by thiazolidinediones. Upon ligand activation, all PPARs bind with the retinoid-X receptor (RXR), and the heterodimer formed thereby binds to peroxisome proliferator response elements (PPREs) in the genome.[4] Suppression of PPAR gene expression by ethanol was described over a decade ago.[5] CE feeding diminishes PPARα/RXR DNA binding in the liver, and ethanol-induced hepatic lipid accumulation can be reversed by treatment with PPARα agonists in mouse and rat models of ethanol feeding.[6] [7] Conversely, CE feeding resulted in worsened liver injury in PPARα-knockout mice versus wild-type mice, indicating that PPARα activation may be protective in ALD.[8] Similarly, hepatocyte RXR deficient mice displayed worsened liver injury with CE.[9]

Osteopontin and PPARα

To date, the mechanism of ethanol-induced decrease in PPARα activation remains controversial. Some evidence suggests that the glycoprotein osteopontin may have a role.[10] Treatment of macrophages with PPARα agonists suppressed osteopontin production and circulating osteopontin was diminished in patients treated with PPARα agonists.[10] Conversely, CE feeding in osteopontin null mice resulted in greater lipid accumulation and liver injury than in wild-type mice, with higher PPARα messenger ribonucleic acid (mRNA) levels.[11]

Adiponectin and PPARα

Another potential mechanism involves adiponectin, an adipocyte-derived hormone that is dysregulated in rats with CE exposure.[12] In vitro studies suggest that adiponectin is a potent stimulator of PPARα DNA binding.[13] Treatment of mice with a pharmacological inhibitor of the inhibitory kappa kinase-2 in a mouse model of diet-induced nonalcoholic steatohepatitis (NASH) maintained adiponectin levels and PPARα activation, strengthening the link between adiponectin and PPARα and suggesting that the dysregulation of NFκB signaling in CE exposure, discussed below, may interface hepatic lipid accumulation along an adiponectin-PPARα axis.[14]

Although compelling, the data linking adiponectin to hepatic lipid accumulation is not without controversy. Adiponectin is known to exert some of its effects via activation of the adenosine monophosphate-activated protein kinase (AMPK), which, in turn, acts to downregulate lipid accumulation by a variety of mechanisms.[15] Briefly, stimulation of AMPK is thought to inactivate acetyl-coA carboxylase, which prevents the formation of malonyl-CoA, itself an inhibitor of the fatty acid transporter carnitine palmitoyl transferase. Treatment of ethanol-fed animals with an AMPK inhibitor (AICAR) prevented lipid accumulation and normalized serum alanine aminotransferase (ALT) levels, suggesting that the beneficial effect of adiponectin may be modulated through adiponectin effects on AMPK.[16] Although these studies were conducted in models of CE, a recent study investigated the effects of metformin, a biguanide pharmaceutical agent known to act in part through AMPK pathway activation, in both AE- and CE-fed mice.[17] Despite robust prevention of hepatic lipid accumulation in mice treated with metformin and AE, AMPK activation was not observed. In metformin-/CE-fed mice, hepatic lipid accumulation remained lower than mice fed ethanol alone, and AMPK activation again appeared unchanged.[17]

Plasminogen Activator Inhibitor-1

Metformin treatment in alcohol-fed mice also correlated with diminished plasminogen-activator-inhibitor-1 (PAI-1) expression, and PAI-1 knockout mice were protected from ethanol-induced liver injury.[17] In support of the notion that inhibition of PAI-1 may be an important mechanism of the protective effects of adiponectin on hepatic lipid accumulation in CE feeding, investigators found that treatment of HepG2 cells with the PPARα agonist fenofibrate suppressed PAI-1 levels.[18]

Oxidant Stress and Lipid Accumulation

Evidence also suggests that hepatic lipid accumulation and PPARα activation are profoundly affected by oxidant stress. An inhibiting effect of antioxidant administration on hepatic lipid accumulation in CE was described almost 40 years ago.[19] Knockout of the p47 NADPH oxidase subunit was able to prevent ethanol induced liver injury in a model of continuous enteral CE feeding.[20] Cytochrome P450 2E1 (CYP2E1), a member of the p450 mixed-oxidase system of xenobiotic metabolizing enzymes, has been proposed as a potential source of oxidant stress in response to ethanol feeding.[21] CYP2E1 mRNA is upregulated by ethanol.[22] However, conflicting experimental results suggest that the role of CYP2E1 is as yet unresolved. Most recently, in an oral CE feeding model, neither CYP2E1 null mice nor wild-type mice fed ethanol and a chemical inhibitor of CYP2E1 developed steatosis.[23] Intriguingly, ethanol caused an upregulation in hepatic PPARα in CYP2E1 null mice, suggesting a role for endogenous CYP2E1 in the negative regulation of PPARα.[23] In distinction, earlier studies found that AE or CE in CYP2E1-knockout mice had no effect on increased lipid accumulation and liver injury.[24] [25]

Other Pathways and Hepatic Lipid Accumulation

The developing picture of decreased PPARα activation and subsequent hepatic lipid accumulation is complicated by observations that PPARγ activation may have a protective effect on ALD. The PPARγ agonist pioglitazone repeatedly prevented injury in rat models of ALD.[26] [27] [28] However, though several studies report a reduction of PPARγ mRNA with ethanol treatment in vivo and in vitro, others report no effect of ethanol on PPARγ protein expression.[29] [30] Indeed, in the studies cited previously, no effect of pioglitazone on PPARγ gene expression was observed in one study, whereas PPARγ mRNA levels were restored by pioglitazone in ethanol-treated animals in a second study.[27] [28] Although studies on a third member of the PPAR family, PPARδ, are limited in ALD, a recent report demonstrated that PPARδ activation ameliorates hepatic steatosis in a mouse model of nonalcoholic fatty liver disease.[31]

An alternative mechanism may involve activation of the peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC1-α). PGC1-α interacts both with PPARγ as well as with the histone deacetylase sirtuin 1 (SIRT1). Both PGC1-α and SIRT1 were suppressed by ethanol, and reversal of these effects (with resveratrol treatment) prevented ALD in a mouse model.[32] [33] This effect of resveratrol was coupled with AMPK activation and increased expression of adiponectin and adiponectin receptors. However, in a rat model of continuous enteral CE feeding, conjunct resveratrol treatment exacerbated liver injury.[34] Sirt1 was recently identified as a regulator of sterol-regulatory element binding protein 1c (SREBP1c).[32] CE upregulated SREBP1c, its downstream targets, and overexpression of SREBP1c caused steatosis in a mouse model.[35] However, ethanol feeding in an SREBP null mouse resulted in only a partial reduction of hepatic triglyceride.[36] Signal transducer and activator of transcription 3 (STAT3) activation may limit SREBP1c activation in ethanol-fed animals, as a hepatocyte-specific STAT3 knockout model accumulated greater lipid and showed increased SREBP1 induction versus wild-type controls.[37] As SREBP1c protein levels and activity may be regulated by PPARα,[38] [39] it is possible that the failure of SREBP1c knockout to completely protect against ethanol-induced effects on lipid accumulation is due to coordinate regulation of multiple pathways of lipid accumulation by PPARα.

Complement

Recent reports implicate components of the complement cascade in CE-induced fatty liver. C3 knockout mice (c3−/−) did not develop CE-induced fatty liver.[40] A second study also described worsening steatosis in ethanol-fed mice lacking either the Complement 5 (C5) or the C3 convertase-inhibiting enzyme decay accelerating factor (DAH).[41] These studies provide an instance of a link between ALD and immune pathways, which is discussed further below.

ETHANOL AND THE TLR4-INNATE IMMUNE SIGNALING AXIS IN KUPFFER CELLS

Toll-like Receptor Signaling Pathways

A second broad area of liver physiology that is impacted by CE exposure involves signaling pathways of innate immunity (Fig. [2]). KCs play a major role in hepatic innate immunity and the development of ALD.[42] KCs, along with other cell types in the liver, express the toll-like receptor 4 (TLR4), which responds to endotoxin and results in production of proinflammatory cytokines such as TNFα.[43] TNFα plays an important role in the pathobiology of ALD, as administration of anti-TNFα antibodies or utilization of a TNF-receptor 1 knockout mouse resulted in diminished liver injury in an enteral CE feeding model.[44]

A major concept in the pathogenesis of liver injury in the setting of CE exposure postulates that endotoxin from commensal gram-negative gut flora enters the hepatic portal vein as a consequence of CE-induced heightened gut permeability, with subsequent stimulation of KCs. ALD has been correlated with increased portal vein endotoxin levels.[45] [46] Gut permeability may be increased by an ethanol-induction of mir212, a microRNA that downregulated proteins of the zona occludens in intestinal cell culture and were higher in human colonic biopsy samples in patients with ALD.[47] Alternatively, studies in other models suggest a role for TNFα, interleukin 6 (IL6), and other inflammatory cytokines in altered gut permeability.[48] [49]

In the circulation, free endotoxin is in equilibrium with endotoxin bound to lipopolysaccharide (LPS) binding protein (LBP). LBP facilitates the dissociation of LPS into a monomeric form that enhances LPS transfer to TLR4 and its associated coreceptors, CD14 and MD-2.[50] Both KC CD14 expression and hepatic LBP-binding protein administration were demonstrated to be upregulated by CE, offering some insight into the manner by which CE confers hypersensitivity to LPS stimulation (LPS hyperresponsiveness.)[51] The role of CE on TLR4 or TLR2 mRNA is more controversial, as CE feeding for several weeks did not result in any change in TLR4 or TLR2 expression.[52] However, another model demonstrated an increase in the mRNA expression of almost all TLRs in response to a shorter term (10 day) ethanol feeding protocol.[53] CD14 knockout mice in an intragastric CE model had less ALT elevation, but had a similar increase in liver-weight to body-weight ratios as wild-type mice.[54] LBP knockout mice fed on an intragastric CE model had diminished ALT, inflammation, and necrosis and diminished liver weight/body weight ratios in comparison to wild-type mice. No changes were observed in CYP2E1, TGFB1, or portal vein endotoxin levels, but IL6 and TNFα was reduced in LBP knockout mice versus controls.[55]

Signaling through the TLR4 receptor complex results in activation of at least two distinct intracellular signaling cascades.[56] The first of these, the MyD88- (myeloid differentiation primary response gene 88) dependent pathway utilizes the common adaptor protein MyD88 that is used by all TLRs with the exception of TLR3.[57] The MyD88-dependent pathway leads to activation of the nuclear factor kappa B (NFκB) and subsequent stimulation of TNFα. A second pathway of TLR4-dependent signaling, the MyD88-independent pathway, converges with a TLR3-signaling pathway utilizing the adaptor molecule toll/interleukin-1 receptor (TIR-) domain containing-adaptor-inducing-IFNB (TRIF). TRIF activation results in production of type I interferons (IFNs) through the interferon regulatory factor 3 (IRF3), and delayed NFκB activation.[58] [59] A recent finding reported from our laboratory is that the hepatoprotective effect of TLR4 knockout is independent of the MyD88 pathway.[60] MyD88-knockout mice developed steatosis and elevated ALTs after CE similar to wild-type mice, though TLR4-knockout mice were protected from this effect. The involvement of the MyD88-independent TLR4 signaling pathway was indicated by upregulation of IRF7, an IRF3-inducible gene, in KCs.[57] A recent study corroborates this finding using TRIF pathway knockout animals, as TRIF knockout mice were protected against alcoholic liver injury, showing diminished lipid accumulation by microscopy and normalized ALT after CE plus endotoxin injection.[61] In that model, the authors argued for an IRF3-dependent mechanism of LPS hyperresponsiveness and TNFα secretion, using strategies including mutation of the IRF3 response element in a TNFα promoter fragment.

The Nuclear Factor Kappa B

The NFκB serves as a master regulator in the inflammatory response. NFκB subunits are normally sequestered in an inactive form, but proinflammatory stimuli such as TLR4 ligand stimulation, cause NFκB activation and TNFα production.[61] Some NFκB activity is essential to prevent massive hepatocyte apoptosis in response to TNFα.[62] [63] NFκB activation in response to ethanol has been widely investigated in many hepatic and nonhepatic cell types. In isolated human monocytes, AE suppresses NFκB activation and the inflammatory response to LPS by inhibiting p65 phosphorylation and IκK activity, but CE causes LPS hypersensitivity and NFκB activation.[64] Changes in LPS sensitivity have been linked to chromatin remodeling in other experimental systems.[65]

Several other mechanisms of regulation of NFκB signaling have been investigated in KCs. Among these, recent work utilizing a myeloid-lineage specific cre (cyclization recombination)-recombinase enzyme to achieve specific deletion of STAT3 in KCs revealed that STAT3 signaling is essential to suppress inflammatory cytokine production from KCs from CE-fed mice.[37] Several lines of evidence implicate oxidative stress as a cause of ethanol-induced LPS hyperresponsiveness in macrophages. Adiponectin, which prevented steatotic change in CE, also exerts modulating effects on KCs, and was shown to downregulate LPS-responsive TNFα secretion in a fashion dependent on NFκB and the transcription factors EGR-1 and AP-1.[66]

Cyclic AMP

Another line of evidence implicates ethanol-induced decreases in cyclic AMP as a mechanism for LPS hyperresponsiveness in macrophages. CE was shown to increase phosphodiesterase 4B (PDE4B), which, in turn, degrades cyclic AMP. Treatment of human and murine macrophage cell lines with an inhibitor of PDE4B diminished the LPS-induced increase in TNFα.[67]

MAPK

Other lines of evidence implicate oxidant stress pathways as mediators of LPS hyperresponsiveness in CE. Knockout of the early growth response 1 (EGR-1) transcription factor conferred protection against the development of liver injury after CE feeding.[68] Following lines of evidence that indicated that extracellular-signal-regulated kinase 1 (ERK-1) promotes LPS hyperresponsiveness in macrophages stimulated with ethanol, potentially by upregulation of EGR-1, Thakur and coworkers[69] examined the role of NADPH-derived reactive oxygen species (ROS) in macrophages. Treatment of macrophages with an inhibitor of NADPH oxidase (DPI) prevented TNFα secretion from macrophages in a p38-dependent manner. However, CE feeding prevented DPI from changing the ratio of phosphorylated p38 observed in pair-fed animals. Administration of DPI suppressed LPS-stimulated ERK phosphorylation, even in ethanol-fed animals, suggesting that ERK phosphorylation is indispensable to TNFα secretion in response to LPS, but that ethanol exerts actions through NADPH-oxidase-independent mechanisms that affect the p38 MAPK and NFκB pathways.[69]

Nuclear Factor/Erythroid Related Factor 2

A potential alternate mechanism may include the nuclear factor/erythroid-related factor 2 (NRF2), a transcription factor implicated in regulation of cellular response to oxidative stress. CE exacerbated liver damage in NRF2( − / − ) mice versus wild-type controls, and was associated with higher circulating levels of TNFα and IL6, possibly through a NADPH-oxidase dependent mechanism.[70] This result extends an earlier finding that NRF2 disruption increased mortality of endotoxin-induced shock in a mouse model.[71] However, NRF2 deficiency was also associated with increased gut permeability after inflammatory brain injury; hence, livers of NRF2 (−/−) mice may be exposed to higher levels of endotoxin.[49]

Macrophage Iron

CE causes iron accumulates in hepatocytes and macrophages.[72] Ethanol upregulates the transferrin receptor in primary rat hepatocytes.[73] CE also may increase gut uptake of iron via downregulation of the iron transport hormonal mediator, hepcidin. Hepcidin, produced by hepatocytes, has been demonstrated to suppress iron uptake by the small bowel, and low levels of hepcidin have been observed in patients with ALD as well as in mouse models of CE feeding.[74] Additionally, alcohol disrupted iron-stimulated production of hepcidin from the liver, thus interrupting a negative feedback loop between serum iron and gut iron absorption.[75]

Iron accumulation in macrophages is associated with enhanced NFκB activation in ethanol feeding models.[76] Administration of iron dextran to CE-fed mice resulted in higher ALT and TNFα, and worsened liver inflammation.[77] Other investigators suggest a role for endotoxin in increasing macrophage free iron, and propose a heme-oxygenase-1-dependent mechanism.[78]

ETHANOL AND IMMUNITY

The liver has a well-characterized role in immunity, containing large numbers of tissue macrophages (KCs), plasmacytoid and myelocytoid dendritic cells (DC), T lymphocytes, natural killer (NK) cells, and natural killer-T cells (NKTs). Virtually all of these cell types have been demonstrated to be affected by CE.[79] Stellate cells have commanded significant interest due to evidence indicating their pivotal role in fibrotic change in the liver. Stellate cells can function as antigen-presenting cells (particularly for lipid-derived antigens), colocalize with T-cells in vivo in response to CCl₄-induced fibrosis, and are able to activate NKT cells.[80] [81]

Broadly speaking, the central role of the endotoxin-mediated inflammatory cascade in ALD occurs in parallel with immunosuppressive effects of ethanol.[82] Ethanol is associated with increased susceptibility to bacterial infections, including salmonella, Listeria, and others, particularly pulmonary infections.[83] Recognition of invading pathogens and initiation of innate and adaptive immune responses relies on the function of antigen-presenting DCs, the function of which is impaired by ethanol.[84] DC populations in the liver are found in an immature phenotype, which may contribute to a tolerogenic environment.[84]

Ethanol Abuse and Antiviral Immunity

Alcohol abuse is a major cofactor for the development of cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B and C, and has been shown to be a predictor of negative outcomes in patients with chronic hepatitis C virus (HCV) or hepatitis B virus (HBV).[85] Several lines of evidence implicate dysregulated cellular signaling events in the increased risk of disease progression in the setting of viral exposure. Ethanol suppresses the effectiveness of IFN therapy as a disease-modifying agent in HCV infection.[86] The molecular mechanisms of these effects remain unclear. Ethanol potentiates HCV viral replicon expression in vitro.[87] Ethanol activates the IFN-response element, P38, and Janus kinases (Jak)/STAT signaling pathways in hepatocyte cell lines and fetal hepatocytes. AE inhibited HCV viral replication, but AE also suppressed the ability of IFN to inhibit HCV viral replication.[88] However, the application of these findings to CE is unclear. In the human hepatoma-derived cell line Huh7, coexpression of HCV core protein and alcohol induction of CYP2E1 additively increased mitochondrial ROS production and cellular death.[89]

Recent work has also prompted the development of an intriguing nexus around antigen presentation in CE exposure. Ethanol-derived oxidative stress inhibited proteolytic activity in cultured hepatocyte cell lines, which decreases the availability of peptide fragments for antigen presentation.[90] Furthermore, ethanol suppressed HCV core peptide activation of the proteasome.[91] Both results point to a mechanism whereby ethanol diminishes the liver's ability to clear viral infection. IFNγ was also found to stimulate proteasome activation in cultured hepatocytes. Again, ethanol suppressed this activation.[92] AE and CE impairs antigen-presentation by DC.[93] This was associated with decreased costimulatory molecule expression in ethanol-exposed dendritic cells. Additionally, some evidence indicates that ethanol and HCV infection have additive inhibitory effects on T cell activation.[94] Immature DCs from patients with chronic HCV infection showed decreased allostimulatory capacity when concordantly exposed to ethanol.[95] A recent report extends this finding, demonstrating that dendritic cells have decreased costimulatory molecule expression and allostimulatory activity against HCV non-structural protein 5 (NS5) protein after CE exposure.[96] Other studies, though, have demonstrated little or no increase in T cell activation and antigen-specific immune responses in HCV or HCV/human immunodeficiency virus (HIV) coinfected individuals who consumed ethanol.[97] Furthermore, ethanol diminished total numbers of splenic, thymic, and dermal DCs.[98] [99] Hepatic DC migration to secondary lymphoid tissue was blocked by ethanol.[100]

T-cells and NK-cells, the effector cells of the of host response to viral infection, are affected by ethanol. In rhesus macaques, ethanol decreased the numbers of CD4 and CD8 T cells in the liver following infection with the simian immunodeficiency virus (SIV).[101] Transplanted T-lymphocytes from rats with ALD-induced inflammation and hepatic necrosis in alcohol-naive rats.[102] Ethanol caused greater T-cell infiltration and increased liver injury in concanavalin-induced T-cell hepatitis, with increased NFκB activation and diminished STAT3 activation, but no change in NK cell activation.[103] Aberrant NFκB signaling and diminished STAT3 signaling in response to CE may prime the liver for more extensive damage upon inflammation, either by increasing hepatocyte apoptosis, or increased antibody-mediated attack on liver cells. This is consistent with reports (above) that show STAT3 suppression of enhanced cytokine production in response to ethanol. Indeed, in other models, NK-cell activation was diminished by CE. Murine cytomegalovirus (MCMV) or polyinosinic/polycytidylic double-stranded RNA (poly I:C), a TLR3 ligand, induced NK cell recruitment into the liver, and CE feeding blunted this response and worsened injury after MCMV infection.[104] Inhibition of immune activity against activated stellate cells by hepatic NK cells may be a pathogenic mechanism in hepatic fibrosis.[105]

Ethanol Abuse and Antiviral Response in Tissues Other than Liver

Our understanding of ethanol's suppression of the host antiviral response is extended by studies on ethanol and viral infections in tissues beyond the liver. CE exacerbates murine influenza infections, with ethanol-fed mice showing inhibition of CD8-T cell response, as well as increased severity of pulmonary lesions in response to murine influenza challenge.[106] In a mouse model of respiratory-syncytial virus infection, virally induced IFNa and IFNb were insufficient to overcome infection after CE.[107] Indeed, ethanol appears to have a deleterious and wide-ranging effect on the development of pulmonary diseases.[108] Ethanol diminished pulmonary response to lipopolysaccharide, including decreased cysteine-X-cysteine (CXC) chemokine expression and leukocyte recruitment.[109] Ethanol also suppressed TNFα production from alveolar macrophages in SIV-infected rhesus macaques.[110]

ALCOHOL AND AUTOIMMUNE HOST RESPONSE

Aside from the pathways of innate immunity described above, ethanol has significant effects on adaptive immunity that contribute to hepatic inflammation and dysfunction via several distinct, though potentially overlapping mechanisms. First, CE results in increased circulation of acetaldehyde and malondialdehyde, both of which can form antigenic adducts (singularly or in tandem) with native liver proteins.[111] Second, the prolonged inflammation, necrosis, and apoptosis present in ALD exposes damaged cellular material to immature antigen-presenting cells in the liver, which may cause autoantibody formation.[112] Supporting this, increased serum TNFα in patients with ALD was associated with higher prevalence of antibodies against oxidized cardiolipin and malondialdehyde-albumin adducts.[113] Autoantibodies were also demonstrated to be more prevalent in patients with ALD than nondrinking alcohol consumers.[114] This study has been verified by others who have described increased immunoglobulin G and immunoglobulin A autoantibodies in patients with ALD versus moderate alcohol- or nonalcohol-consuming control subjects.[115]

Sixty to eighty percent of patients with alcoholic hepatitis or cirrhosis may have antiphospholipid antibodies (aPl). A recent study by Vay et al[112] offers good evidence that aPl in ALD recognize oxidized phosphatidylserine residues on apoptotic cell membranes. Incubation of aPl serum from ALD patients with synthesized phosphatidyl serine micelles diminished their ability to bind apoptotic cells, and serum from ALD patients was able to target the plasma membrane of apoptotic HepG2 cells stimulated with ethanol.[112]

Anti-CYP2E1 antibodies are also highly prevalent in patients with ALD. In one study, up to 86% of cirrhotic patients had sera with positivity for immunoreactivity against CYP2E1.[116] Anti-cardiolipin antibodies are also reported to occur more frequently in patients with ALD than liver disease from other causes or healthy control subjects.[117] Antibodies are produced in the adaptive immune response by B-lymphocytes. The effect of ethanol on B cells remains controversial. Although polyclonal hyperglobulinemia and increased circulating autoantibodies are found in patients suffering from alcoholism, recent investigations in a mouse model of chronic ethanol consumption demonstrates little effect of ethanol on B cell numbers.[118]

SUMMARY AND CONCLUSIONS

The disease-promoting effects of ethanol consumption on hepatic parenchymal and nonparenchymal cells is a complex phenomenon that incorporates changes at many different levels. On the one hand, the passage of ethanol through the metabolic pathways toward acetaldehyde or through the CYP2E1 system alters the cellular redox state, creates ROS, and alters lipid metabolic pathways to favor lipid accumulation. Although these changes are priming the hepatocyte to have increased susceptibility to TNFα-mediated apoptosis, ethanol is simultaneously inducing hyperresponsiveness to gut-derived endotoxin in hepatic Kupffer cells. The inflammatory effect of these changes induces recruitment of other cell types, including T cells, NK cells, and NKT cells, and the production of autoantibodies that further exacerbate liver injury. In the past decade, the use of transgenic mouse models, including cre-lox tissue specific knockout/knock-in models, has offered great insight into disease mechanisms. Future work promises additional insight toward the development of treatment strategies for the array of disease caused by alcohol use.

ACKNOWLEDGEMENTS

Bharath Nath is an M.D./Ph.D. student and is supported by NIH grant F30 AA017030.

ABBREVIATIONS

• AE acute ethanol

• ALD alcoholic liver disease

• ALT alanine aminotransferase

• AMPK adenosine monophosphate-activated protein kinase

• aPl antiphospholipid antibodies

• CE chronic ethanol

• CYP2E1 cytochrome P450 2E1

• DC dendritic cells

• EGR1 early growth response 1

• ERK extracellular signal regulated kinase

• HBV hepatitis B virus

• HCV hepatitis C virus

• IFN interferon

• IL interleukin

• IRF interferon regulatory factor

• Jak Janus kinases

• KC Kupffer cells

• LBP lipopolysaccharide-binding protein

• LPS lipopolysaccharide

• LXR liver X receptor

• MAPK mitogen-activated protein kinase

• MCMV murine cytomegalovirus

• mRNA messenger ribonucleic acid

• MYD88 myeloid differentiation primary response gene 88

• NFκB nuclear factor kappa B

• NRF2 nuclear factor/erythroid related factor 2

• NK natural killer

• NKT natural killer T

• PAI-1 plasminogen activator inhibitor-1

• PGC1-α peroxisome proliferator gamma coactivator 1-α

• poly I:C polyinosinic/polycytidylic double-stranded RNA

• PPAR peroxisome proliferator-activated receptor

• ROS reactive oxygen species

• RXR retinoid X receptor

• SREBP sterol-regulatory element binding protein

• SIRT1 sirtuin 1

• STAT signal transducer and activator of transcription

• STAT3 signal transducer and activator of transcription 3

• TLR toll-like receptor

• TNFα tumor necrosis factor-α

• TRIF toll/interleukin-1 receptor (TIR) domain containing adaptor inducing interferon B

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Gyongyi SzaboM.D. Ph.D. 

Director of Hepatology and Liver Center, Department of Medicine, University of Massachusetts Medical School

364 Plantation Street, LRB 215, Worcester, MA 01605

Email: Gyongyi.Szabo@umassmed.edu

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Gyongyi SzaboM.D. Ph.D. 

Director of Hepatology and Liver Center, Department of Medicine, University of Massachusetts Medical School

364 Plantation Street, LRB 215, Worcester, MA 01605

Email: Gyongyi.Szabo@umassmed.edu