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Full-Text Articles in Medicine and Health Sciences
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Katherine A. Fitzgerald
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 …
Chronic Alcohol-Induced Microrna-155 Contributes To Neuroinflammation In A Tlr4-Dependent Manner In Mice, Dora Lippai, Shashi Bala, Timea Csak, Evelyn A. Kurt-Jones, Gyongyi Szabo
Chronic Alcohol-Induced Microrna-155 Contributes To Neuroinflammation In A Tlr4-Dependent Manner In Mice, Dora Lippai, Shashi Bala, Timea Csak, Evelyn A. Kurt-Jones, Gyongyi Szabo
Gyongyi Szabo
INTRODUCTION: Alcohol-induced neuroinflammation is mediated by pro-inflammatory cytokines and chemokines including tumor necrosis factor-alpha (TNFalpha), monocyte chemotactic protein-1 (MCP1) and interleukin-1-beta (IL-1beta). Toll-like receptor-4 (TLR4) pathway induced nuclear factor-kappaB (NF-kappaB) activation is involved in the pathogenesis of alcohol-induced neuroinflammation. Inflammation is a highly regulated process. Recent studies suggest that microRNAs (miRNAs) play crucial role in fine tuning gene expression and miR-155 is a major regulator of inflammation in immune cells after TLR stimulation. AIM: To evaluate the role of miR-155 in the pathogenesis of alcohol-induced neuroinflammation. METHODS: Wild type (WT), miR-155- and TLR4-knockout (KO) mice received 5% ethanol-containing or isocaloric …
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Gyongyi Szabo
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 …
An Essential Role For Monocyte Chemoattractant Protein-1 In Alcoholic Liver Injury: Regulation Of Proinflammatory Cytokines And Hepatic Steatosis In Mice, Pranoti Mandrekar, Aditya Ambade, Arlene Lim, Gyongyi Szabo, Donna Catalano
An Essential Role For Monocyte Chemoattractant Protein-1 In Alcoholic Liver Injury: Regulation Of Proinflammatory Cytokines And Hepatic Steatosis In Mice, Pranoti Mandrekar, Aditya Ambade, Arlene Lim, Gyongyi Szabo, Donna Catalano
Gyongyi Szabo
The importance of chemokines in alcoholic liver injury has been implicated. The role of the chemokine, monocyte chemoattractant protein-1 (MCP-1), elevated in patients with alcoholic liver disease is not yet understood. Here, we evaluated the pathophysiological significance of MCP-1 and its receptor, chemokine (C-C motif) receptor 2 (CCR2), in alcoholic liver injury. The Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP-1-deficient knockout (KO) mice for 6 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. MCP-1 was increased in Kupffer cells (KCs) as …
Diverse Regulation Of Nf-Kappab And Peroxisome Proliferator-Activated Receptors In Murine Nonalcoholic Fatty Liver, Laszlo Romics, Karen Kodys, Angela Dolganiuc, Lucia Graham, Arumugam Velayudham, Pranoti Mandrekar, Gyongyi Szabo
Diverse Regulation Of Nf-Kappab And Peroxisome Proliferator-Activated Receptors In Murine Nonalcoholic Fatty Liver, Laszlo Romics, Karen Kodys, Angela Dolganiuc, Lucia Graham, Arumugam Velayudham, Pranoti Mandrekar, Gyongyi Szabo
Gyongyi Szabo
Fatty liver is highly sensitive to inflammatory activation. Peroxisome proliferator-activated receptors (PPAR) have anti-inflammatory effects and regulate lipid metabolism in the fatty liver. We hypothesized that fatty liver leads to endotoxin sensitivity through an imbalance between pro- and anti-inflammatory signals. Leptin-deficient, ob/ob mice and their lean littermates were challenged with single or double insults and pro- and anti-inflammatory pathways were tested on cytokine production and activation of nuclear regulatory factors NF-kappaB and peroxisome proliferator receptor element (PPRE). Ob/ob mice produced significantly higher serum tumor necrosis factor alpha (TNF-alpha) and interleukin (IL) 6 and showed increased hepatic NF-kappaB activation compared to …
Microrna Expression Profile In Lieber-Decarli Diet-Induced Alcoholic And Methionine Choline Deficient Diet-Induced Nonalcoholic Steatohepatitis Models In Mice, Angela Dolganiuc, Jan Petrasek, Karen Kodys, Donna Catalano, Pranoti Mandrekar, Arumugam Velayudham, Gyongyi Szabo
Microrna Expression Profile In Lieber-Decarli Diet-Induced Alcoholic And Methionine Choline Deficient Diet-Induced Nonalcoholic Steatohepatitis Models In Mice, Angela Dolganiuc, Jan Petrasek, Karen Kodys, Donna Catalano, Pranoti Mandrekar, Arumugam Velayudham, Gyongyi Szabo
Gyongyi Szabo
BACKGROUND: Alcoholic and nonalcoholic steatohepatitis are leading causes of liver diseases worldwide. While of different etiology, these share common pathophysiological mechanisms and feature abnormal fat metabolism, inflammation and fibrosis. MicroRNAs (miRNA) are highly conserved noncoding RNAs that control gene expression at the post-transcriptional level either via the degradation of target mRNAs or the inhibition of translation. Each miRNA controls the expression of multiple targets; miRNAs have been linked to regulation of lipid metabolism and inflammation. METHODS: We fed Lieber-DeCarli alcohol or methionine-choline-deficient (MCD) diets to C57Bl6 and analyzed livers for histopathology, cytokines by ELISA, alanine aminotransferase (ALT) by biochemical assay, …
The Critical Role Of Toll-Like Receptor (Tlr) 4 In Alcoholic Liver Disease Is Independent Of The Common Tlr Adapter Myd88, Istvan Hritz, Pranoti Mandrekar, Arumugam Velayudham, Donna Catalano, Angela Dolganiuc, Karen Kodys, Evelyn Kurt-Jones, Gyongyi Szabo
The Critical Role Of Toll-Like Receptor (Tlr) 4 In Alcoholic Liver Disease Is Independent Of The Common Tlr Adapter Myd88, Istvan Hritz, Pranoti Mandrekar, Arumugam Velayudham, Donna Catalano, Angela Dolganiuc, Karen Kodys, Evelyn Kurt-Jones, Gyongyi Szabo
Gyongyi Szabo
The Toll-like receptor 4 (TLR4) that recognizes endotoxin, a trigger of inflammation in alcoholic liver disease (ALD), activates two signaling pathways utilizing different adapter molecules: the common TLR adapter, myeloid differentiation factor 88 (MyD88), or Toll/interleukin immune-response-domain-containing adaptor inducing interferon (IFN)-beta. The MyD88 pathway induces proinflammatory cytokine activation, a critical mediator of ALD. Here we evaluated the role of MyD88 in alcohol-induced liver injury in wild-type, TLR2-deficient, TLR4-deficient, or MyD88-deficient (knockout [KO]) mice after administration of the Lieber-De-Carli diet (4.5% volume/volume ethanol) or an isocaloric liquid control diet for 5 weeks. Alcohol feeding resulted in a significant increase in serum …