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Rsa 2004: Combined Basic Research Satellite Symposium - Session Two: Toll-Like Receptors And Organ Damage, Pranoti Mandrekar, Stephen Pruett, Gavin Arteel, Geoffrey Thiele, Gyongyi Szabo

Gyongyi Szabo

This article summarizes the proceedings of the RSA 2004 Combined Basic Research Satellite Meeting convened at the Westin Bayshore Resort and Marina, Vancouver, BC. The session "Toll-like receptors and organ damage" featured three speakers and was chaired by Drs. Steve Nelson and Craig McClain. The presentations were 1) Toll-like receptor mediated macrophage activation-modulation by acute alcohol administration in mice by Stephen Pruett, 2) Alcoholic liver disease: Crossroads of TLRs and oxidative stress by Gavin Arteel, and 3) The role of TLR2 and TLR4-mediated signals in liver injury by Gyongyi Szabo.

Critical Role Of Toll-Like Receptors And The Common Tlr Adaptor, Myd88, In Induction Of Granulomas And Liver Injury, Arumugam Velayudham, Istvan Hritz, Angela Dolganiuc, Pranoti Mandrekar, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND/AIMS: Toll-like receptors (TLR) recognize pathogens and regulate innate immune activation. Here, we investigated the roles of TLR9 and the common TLR adaptor, MyD88, in liver injury.

METHODS: C57BL6, TLR9(-/-), IFNgamma(-/-) or MyD88(-/-) mice were primed with Propionibacterium acnes, TLR9 (CpG) or TLR2 (lipoteichoic acid) ligands followed by LPS challenge. ALT, cytokines and liver histology were assessed.

RESULTS: Selective priming through TLR9 but not TLR2 induced granulomas, elevated serum ALT, and sensitized C57BL6 mice to increased LPS-induced serum IL-6, IL-12 and IFNgamma levels. Further, TLR2 and TLR9 ligands synergized in induction of granulomas and sensitization to LPS-induced inflammation. IFNgamma induction …

Signalling Pathways In Alcohol-Induced Liver Inflammation, Pranoti Mandrekar, Gyongyi Szabo

Gyongyi Szabo

The pathogenesis of alcoholic liver injury involves interactions of several intracellular signalling pathways in different cell types of the liver. Alcohol-induced sensitization of liver macrophages to portal endotoxin/lipopolysaccharide (LPS) is considered a hallmark of alcoholic liver disease (ALD). Intracellular mechanisms associated with LPS-induced signalling play a crucial role in the initiation and progression of alcoholic liver injury, and are being extensively explored. LPS recognition by Toll-like receptor 4 (TLR4) on macrophages and other cell types in the liver, activation of downstream signalling pathways culminating in activation of transcription factors such as NFkappaB, AP-1 leads to increased inflammatory cytokine production in …

Increased Lipopolysaccharide Sensitivity In Alcoholic Fatty Livers Is Independent Of Leptin Deficiency And Toll-Like Receptor 4 (Tlr4) Or Tlr2 Mrna Expression, Laszlo Romics, Pranoti Mandrekar, Karen Kodys, Arumugam Velayudham, Yvonne Drechsler, Angela Dolganiuc, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND: Both alcoholic (AFL) and nonalcoholic (NAFL) fatty livers show increased sensitivity to endotoxin-induced injury. Lipopolysaccharide (LPS) is recognized by toll-like receptor 4 (TLR4), whereas lipopeptide triggers TLR2 to induce common downstream activation of nuclear factor (NF)-kappaB and pro-inflammatory pathways that are activated in AFL and NAFL. METHODS: Serum alanine aminotransferase (ALT), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 levels; hepatic NF-kappaB activity; and expression of TLR2, TLR4, inducible nitric oxide synthase (iNOS), and heme oxygenase (HO)-1 mRNAs were investigated in lean and leptin-deficient ob/ob mice after LPS challenge in combination with acute or chronic alcohol feeding. RESULTS: Increased LPS …

Selective Priming To Toll-Like Receptor 4 (Tlr4), Not Tlr2, Ligands By P. Acnes Involves Up-Regulation Of Md-2 In Mice, Laszlo Romics, Angela Dolganiuc, Karen Kodys, Yvonne Drechsler, Shilpa Oak, Arumugam Velayudham, Pranoti Mandrekar, Gyongyi Szabo

Gyongyi Szabo

Lipopolysaccharide (LPS) triggers cytokine production through Toll-like receptor 4 (TLR4), which shares downstream signaling pathways with TLR2. We investigated the roles of TLR2 and TLR4 in Propionibacterium acnes (P. acnes)-primed, LPS-induced liver damage using selective TLR ligands. Stock LPS induced interleukin 8 in both TLR4- and TLR2-expressing human embryonic kidney (HEK) 293 cells. Purified LPS (TLR4 ligand) activated HEK/TLR4 cells, while peptidoglycan and lipoteichoic acid (TLR2 ligands) activated HEK/TLR2 cells, respectively. In mice, P. acnes priming resulted in increased liver messenger RNA (mRNA) and serum levels of tumor necrosis factor alpha, interleukin 12, and interferon gamma (IFN-gamma) by both stock …

Acute Alcohol Inhibits The Induction Of Nuclear Regulatory Factor Kappa B Activation Through Cd14/Toll-Like Receptor 4, Interleukin-1, And Tumor Necrosis Factor Receptors: A Common Mechanism Independent Of Inhibitory Kappa B Alpha Degradation, Pranoti Mandrekar, Angela Dolganiuc, Gary Bellerose, Karen Kodys, Laszlo Romics, Rabia Nizamani, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND: Nuclear translocation and DNA binding of the nuclear factor kappaB (NF-kappaB) is an early event in inflammatory cell activation in response to stimulation with bacterial components or cytokines. Cell activation via different receptors culminates in a common pathway leading to NF-kappaB activation and proinflammatory cytokine induction. We have previously shown that acute alcohol inhibits NF-kappaB activation by lipopolysaccharide (LPS) in human monocytes. Here we investigated whether acute alcohol treatment of human monocytes also inhibits NF-kappaB when induced through activation of the interleukin (IL)-1 or tumor necrosis factor (TNF) receptors. METHODS: Human peripheral blood monocytes were treated with LPS, TNFalpha, …

The Emerging Role Of Toll-Like Receptor Pathways In Surgical Diseases, Laszlo Romics, Gyongyi Szabo, John Calvin Coffey, Jiang Huai Wang, Henry Paul Redmond

Gyongyi Szabo

OBJECTIVE: To outline the emerging significance of Toll-like receptor (TLR) signaling pathways in surgical diseases. DATA

SOURCES: A systematic review of the literature was undertaken by searching the MEDLINE database for the period 1966 to 2005 without language restriction.

STUDY SELECTION: Original or review articles that described experimental data on the activation of TLR signaling pathways in surgically relevant diseases were selected for inclusion in this review.

DATA EXTRACTION: Data were obtained from peer-reviewed articles and references.

DATA SYNTHESIS: The role of TLRs in the recognition of pathogens renders them a key figure in the activation of both innate and …

Hepatitis C Core And Nonstructural 3 Proteins Trigger Toll-Like Receptor 2-Mediated Pathways And Inflammatory Activation, Angela Dolganiuc, Shilpa Oak, Karen Kodys, Douglas Golenbock, Robert Finberg, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND AND AIMS: Recent evidence suggests that toll-like receptors (TLRs) recognize certain viruses. We reported that hepatitis C virus (HCV) core and nonstructural 3 (NS3) proteins activate inflammatory pathways in monocytes. The aim of this study was to investigate the role of TLRs in innate immune cell activation by core and NS3 proteins. METHODS: Human monocytes, human embryonic kidney cells transfected with TLR2, and peritoneal macrophages from TLR2, MyD88 knockout, and wild-type mice were studied to determine intracellular signaling and proinflammatory cytokine induction by HCV proteins. RESULTS: HCV core and NS3 proteins triggered inflammatory cell activation via the pattern recognition …

Viral And Host Factors Induce Macrophage Activation And Loss Of Toll-Like Receptor Tolerance In Chronic Hcv Infection, Angela Dolganiuc, Oxana Norkina, Karen Kodys, Donna Catalano, Gennadiy Bakis, Christopher Marshall, Pranoti Mandrekar, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: Persistent inflammation contributes to progression of liver damage in chronic HCV (cHCV) infection. Repeated exposure to toll-like receptor (TLR) ligands results in tolerance, a protective mechanism aimed at limiting inflammation.

METHODS: Monocytes/macrophages were repeatedly stimulated via proinflammatory cytokine-inducing TLRs and evaluated for activation markers.

RESULTS: Unlike monocytes of controls or patients with nonalcoholic steatohepatitis, the monocytes of cHCV patients were hyperresponsive and failed to show homo- or heterotolerance to TLR ligands, manifested by elevated tumor necrosis factor (TNF)-alpha production. Serum levels of interferon (IFN)-gamma, endotoxin (TLR4 ligand), and HCV core protein (TLR2 ligand) were elevated in cHCV …

The Role Of Plasmacytoid Dendritic Cell-Derived Ifn Alpha In Antiviral Immunity, Gyongyi Szabo, Angela Dolganiuc

Gyongyi Szabo

Viral infections represent a major source of acute and chronic human disease. The immune system plays a central role in the elimination of viruses through its ability to recognize pathogens and to induce virus-specific cellular activation, accompanied by a robust production of soluble molecules with antiviral effects. Interferons are among the most powerful natural soluble antiviral molecules. Upon viral infection, interferons are produced by a variety of cell types, with immune cells being the main contributors. The immune system works as a well-orchestrated team composed of multiple cell types. The mechanisms of intercellular cooperation that includes dendritic cells (DCs), their …

Toll-Like Receptors, Gyongyi Szabo, Pranoti Mandrekar

Gyongyi Szabo

Szabo G, Mandrekar P. Toll-like Receptors. In Signaling Pathways in Liver Diseases. Eds., JF Dufour, PA Clavien. 2nd ed. Springer, 2010, p. 149-159. ISBN 3642001491, 9783642001499.

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