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Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis.

Guo J, Friedman SL - Fibrogenesis Tissue Repair (2010)

Bottom Line: In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling.In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis.Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Liver Diseases, Mount Sinai Hospital, Mount Sinai School of Medicine, New York, NY, USA. scott.friedman@mssm.edu.

ABSTRACT
Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus

Schematic overview of Toll-like receptor (TLR)4 signaling pathway. LPS interacts with circulating LPS-binding protein (LBP) and binds to TLR4 on the cell membrane with two co-receptors (CD14 and myeloid differentiation protein (MD)2), activating myeloid differentiation factor (MyD)88-dependent and (MyD)88-independent TLR4 signaling via different adaptor proteins. The MyD88-dependent pathway signals through activation of iκB kinase (IKK) and mitogen activated protein kinase (MAPK) pathways, which in turn leads to activation of transcription factors nuclear factor (NF)-κB and activator protein (AP)-1, respectively, and controls the expression of pro-inflammatory cytokines and other immune related genes. In addition, phosphatidylinositol 3-kinase (PI3K) and AKT are also important factors downstream of MyD88 that mediate NF-κB activation. The MyD88-independent pathway is mediated by the TIR domain-containing adaptor inducing interferon-β (TRIF), which activates interferon regulatory (IRF)3 and induces the expression of interferon (IFN)-β and IFN-responsive genes
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Figure 1: Schematic overview of Toll-like receptor (TLR)4 signaling pathway. LPS interacts with circulating LPS-binding protein (LBP) and binds to TLR4 on the cell membrane with two co-receptors (CD14 and myeloid differentiation protein (MD)2), activating myeloid differentiation factor (MyD)88-dependent and (MyD)88-independent TLR4 signaling via different adaptor proteins. The MyD88-dependent pathway signals through activation of iκB kinase (IKK) and mitogen activated protein kinase (MAPK) pathways, which in turn leads to activation of transcription factors nuclear factor (NF)-κB and activator protein (AP)-1, respectively, and controls the expression of pro-inflammatory cytokines and other immune related genes. In addition, phosphatidylinositol 3-kinase (PI3K) and AKT are also important factors downstream of MyD88 that mediate NF-κB activation. The MyD88-independent pathway is mediated by the TIR domain-containing adaptor inducing interferon-β (TRIF), which activates interferon regulatory (IRF)3 and induces the expression of interferon (IFN)-β and IFN-responsive genes

Mentions: TLRs mediate a tightly integrated signal transduction cascade linking a series of protein-protein interactions with their ligands, receptors, co-receptors and adaptor proteins to convey downstream signals that control transcription [4] (Figure 1). Genes regulated by TLRs include cytokines and proteins controlling innate and adaptive immunity, cell survival and apoptosis, and fibrogenesis.


Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis.

Guo J, Friedman SL - Fibrogenesis Tissue Repair (2010)

Schematic overview of Toll-like receptor (TLR)4 signaling pathway. LPS interacts with circulating LPS-binding protein (LBP) and binds to TLR4 on the cell membrane with two co-receptors (CD14 and myeloid differentiation protein (MD)2), activating myeloid differentiation factor (MyD)88-dependent and (MyD)88-independent TLR4 signaling via different adaptor proteins. The MyD88-dependent pathway signals through activation of iκB kinase (IKK) and mitogen activated protein kinase (MAPK) pathways, which in turn leads to activation of transcription factors nuclear factor (NF)-κB and activator protein (AP)-1, respectively, and controls the expression of pro-inflammatory cytokines and other immune related genes. In addition, phosphatidylinositol 3-kinase (PI3K) and AKT are also important factors downstream of MyD88 that mediate NF-κB activation. The MyD88-independent pathway is mediated by the TIR domain-containing adaptor inducing interferon-β (TRIF), which activates interferon regulatory (IRF)3 and induces the expression of interferon (IFN)-β and IFN-responsive genes
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984459&req=5

Figure 1: Schematic overview of Toll-like receptor (TLR)4 signaling pathway. LPS interacts with circulating LPS-binding protein (LBP) and binds to TLR4 on the cell membrane with two co-receptors (CD14 and myeloid differentiation protein (MD)2), activating myeloid differentiation factor (MyD)88-dependent and (MyD)88-independent TLR4 signaling via different adaptor proteins. The MyD88-dependent pathway signals through activation of iκB kinase (IKK) and mitogen activated protein kinase (MAPK) pathways, which in turn leads to activation of transcription factors nuclear factor (NF)-κB and activator protein (AP)-1, respectively, and controls the expression of pro-inflammatory cytokines and other immune related genes. In addition, phosphatidylinositol 3-kinase (PI3K) and AKT are also important factors downstream of MyD88 that mediate NF-κB activation. The MyD88-independent pathway is mediated by the TIR domain-containing adaptor inducing interferon-β (TRIF), which activates interferon regulatory (IRF)3 and induces the expression of interferon (IFN)-β and IFN-responsive genes
Mentions: TLRs mediate a tightly integrated signal transduction cascade linking a series of protein-protein interactions with their ligands, receptors, co-receptors and adaptor proteins to convey downstream signals that control transcription [4] (Figure 1). Genes regulated by TLRs include cytokines and proteins controlling innate and adaptive immunity, cell survival and apoptosis, and fibrogenesis.

Bottom Line: In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling.In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis.Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Liver Diseases, Mount Sinai Hospital, Mount Sinai School of Medicine, New York, NY, USA. scott.friedman@mssm.edu.

ABSTRACT
Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus