TRIF and IRF-3 Binding to the TNF Promoter Results in Macrophage TNF Dysregulation and Steatosis Induced by Chronic Ethanol

Zhao, Xuejun; Dong, Qing; Bindas, J.; Piganelli, Jon D.; Magill, Amy; Reiser, Jakob; Kolls, Jay K.

doi:10.4049/jimmunol.181.5.3049

Cited by 106 publications

(100 citation statements)

References 35 publications

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“…1E) at levels between 2 and 3 ng/ml. LPS signaling through TLR4 can drive TNF-a expression through activation of NF-kB, IFN regulatory factor-3, and AP-1 binding sites for which are all present in the TNF-a promoter (59). The observation that SHP-1 inhibition does not enhance the already high levels of TNF-a (.10-fold higher than GM-CSF-induced levels), combined with the fact that there are at least three pathways through which TLR4 can drive TNF-a expression, suggests that SHP-1 may not be the rate limiting step.…”

Section: Discussionmentioning

confidence: 99%

The Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-1 Is an Intrinsic Central Regulator of Dendritic Cell Function

Ramachandran

Song

Lapteva

et al. 2011

The Journal of Immunology

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Dendritic cells (DCs) initiate proinflammatory or regulatory T cell responses, depending on their activation state. Despite extensive knowledge of DC-activating signals, the understanding of DC inhibitory signals is relatively limited. We show that Src homology region 2 domain-containing phosphatase-1 (SHP-1) is an important inhibitor of DC signaling, targeting multiple activation pathways. Downstream of TLR4, SHP-1 showed increased interaction with several proteins including IL-1R–associated kinase-4, and modulated LPS signaling by inhibiting NF-κB, AP-1, ERK, and JNK activity, while enhancing p38 activity. In addition, SHP-1 inhibited prosurvival signaling through AKT activation. Furthermore, SHP-1 inhibited CCR7 protein expression. Inhibiting SHP-1 in DCs enhanced proinflammatory cytokines, IL-6, IL-12, and IL-1β production, promoted survival, and increased DC migration to draining lymph nodes. Administration of SHP-1–inhibited DCs in vivo induced expansion of Ag-specific cytotoxic T cells and inhibited Foxp3+ regulatory T cell induction, resulting in an enhanced immune response against pre-established mouse melanoma and prostate tumors. Taken together, these data demonstrate that SHP-1 is an intrinsic global regulator of DC function, controlling many facets of T cell-mediated immune responses.

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Section: Discussionmentioning

confidence: 99%

The Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-1 Is an Intrinsic Central Regulator of Dendritic Cell Function

Ramachandran

Song

Lapteva

et al. 2011

The Journal of Immunology

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“…Acetaldehyde contributes to alter intestinal barrier function and to promote endotoxin translocation by disrupting tight and adherens junctions in human colonic mucosa [144] via increasing tyrosine phosphorylation of occludin and E-cadherin. The mechanism of acetaldehyde-induced alteration of gut permeability remains unclear, although acute ethanol exposure upregulates miRNA-212 in enterocytes and this is correlated with zonula occludens-1 protein downregulation [145][146][147][148][149][150] . LPS interacts with toll-like receptor (TLR)4 to activate the MyD88-dependent and -independent (TRIF/IRF-3) signaling pathways and induces Kupffer cells to release ROS and an array of proinflammatory cytokines and chemokines including IL-1β, TNF-α, IL-6, IL-8, macrophage chemotactic protein (MCP)-1, and RANTES (regulated normal T cell expressed and secreted) [151] .…”

Section: Ethanol Oxidation and Activation Of Innate And Adaptive Immumentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

402

339

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Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

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“…Phosphorylated IRF3 induces IFN-β during viral infection, but may also contribute to inflammatory cytokine response to LPS (7). IRF3 also promotes apoptosis in virus-infected cells through association with proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] (8).…”

mentioning

confidence: 99%

STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease

Petrášek

Iracheta-Vellve

Csák

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

373

318

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Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3), a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of STING prevented IRF3 phosphorylation by ethanol or ER stress, and absence of IRF3 prevented hepatocyte apoptosis. The pathogenic role of IRF3 in ALD was independent of inflammation or Type-I interferons. Thus, STING and IRF3 are key determinants of ALD, linking ER stress signaling with the mitochondrial pathway of hepatocyte apoptosis. A lcoholic liver disease (ALD) affects over 140 million people worldwide, and currently there is no effective treatment. Acute alcohol consumption induces fatty liver and excessive alcohol use causes progression to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Dysregulation of innate immunity and liver inflammation, triggered by the translocation of gut-derived endotoxin [lipopolysaccharide (LPS)] to the liver, represent major contributors to ALD (1). The recognition of gut-derived LPS by Kupffer cells (KC) requires the Toll-like receptor 4 (TLR4), which triggers two downstream pathways. The TLR4/ myeloid differentiation primary response gene 88 (MyD88) pathway activates transcription of inflammatory cytokines, whereas TLR4/TRAM/TRIF [TIR domain-containing adaptor inducing interferon-beta (TRIF)-related adaptor molecule (TRAM)] triggers Type-I interferons (IFN) regulatory factor 3 (IRF3) to induce IFN (2). The essential role of the TLR4 signaling in ALD was demonstrated in mice lacking functional TLR4 that showed attenuation of alcoholic steatohepatitis (3, 4). In previous studies, we reported that the MyD88-dependent pathway was dispensable for ALD (4) and observed complete protection from alcohol-induced inflammation, steatosis, and injury in mice deficient in IRF3 (5), suggesting that the pathogenic effects of TLR4 in ALD were mediated via the TRAM/TRIF-dependent pathway. However, the mechanisms by which IRF3 causes ALD remain obscure.IRF3 is a constitutively expressed transcription factor that resides in the cytoplasm and dimerizes and translocates to the nucleus upon phosphorylation (6). Phosphorylated IRF3 induces IFN-β during viral infection, but may also contribute to inflammatory cytokine response to LPS (7). IRF3 also promotes apoptosis in virus-infected cells through association with proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] (8). To elucidate the mechanism by which IRF3 determines ALD, we asked three fundamental questions. F...

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TRIF and IRF-3 Binding to the TNF Promoter Results in Macrophage TNF Dysregulation and Steatosis Induced by Chronic Ethanol

Cited by 106 publications

References 35 publications

The Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-1 Is an Intrinsic Central Regulator of Dendritic Cell Function

The Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-1 Is an Intrinsic Central Regulator of Dendritic Cell Function

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease

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