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The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases

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Abstract

Toll-like receptor 4 (TLR4) is a pattern recognition receptor that functions as lipopolysaccharide (LPS) sensor and whose activation results in the production of several pro-inflammatory, antiviral, and anti-bacterial cytokines. TLR4 is expressed in several cells of healthy liver. Despite the constant confrontation of hepatic TLR4 with gut-derived LPS, the normal liver does not show signs of inflammation due to its low expression of TLR4 and ability to modulate TLR4 signaling. Nevertheless, there is accumulating evidence that altered LPS/TLR4 signaling is a key player in the pathogenesis of many chronic liver diseases (CLD). In this review, we first describe TLR4 structure, ligands, and signaling. Later, we review liver expression of TLR4 and discuss the role of LPS/TLR4 signaling in the pathogenesis of CLD such as alcoholic liver disease, nonalcoholic fatty liver disease, chronic hepatitis C, chronic hepatitis B, primary sclerosing cholangitis, primary biliary cirrhosis, hepatic fibrosis, and hepatocarcinoma.

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Abbreviations

Akt:

Serine/threonine protein kinase

ALD:

Alcoholic liver disease

Anti-BEC-Ab:

Antibiliary epithelial cell antibodies

AP-1:

Activator protein 1

ATF3:

Activating transcription factor-3

BAMBI:

Bone morphogenetic protein and activin membrane-bound inhibitor

Bcl-3:

B cell leukemia-3

BEC:

Biliary epithelial cell

CCL:

Chemokine

CCl4 :

Carbon tetrachloride

CLD:

Chronic liver diseases

CYLD:

Cylindromatosis protein

DAMP:

Damage-associated molecular patterns

DEN:

Diethylnitrosamine

DUBA:

De-ubiquitinating enzyme A

ERK:

Extracellular signal-regulated kinase

GSK-3β:

Glycogen synthase kinase-3β

HBV:

Hepatitis B virus

HCC:

Hepatocarcinoma

HCV:

Hepatitis C virus

HSC:

Hepatic stellate cell

ICAM:

Intercellular cell adhesion molecule

IFN:

Interferon

IKK:

Inhibitor of NF-κB kinase

IL:

Interleukin

IRAK:

Interleukin-1 receptor-associated kinase

IRF:

Interferon regulatory factor

IκBα:

Inhibitor of NF-κB

JNK:

C-Jun N-terminal kinase

KC:

Kupffer cells

LBP:

LPS binding protein

LPS:

Lipopolysaccharide

MCDD:

Methionine- and choline-deficient diet

miR:

MicroRNA

MyD88:

Myeloid differentiation factor 88

MyD88s:

Splice variant of MyD88

NAFLD:

Non-alcoholic fatty liver disease

NEMO:

NF-κB essential modifier

NF-κB:

Nuclear factor κB

PAMP:

Pathogen-associated molecular pattern

PBC:

Primary biliary cirrhosis

PI3K:

Phosphatidylinositol 3-kinase

Pin:

Peptidyl-prolyl isomerase

PRR:

Pattern recognition receptor

PSC:

Primary sclerosing cholangitis

RIP:

Receptor-interacting serine–threonine kinase

ROS:

Reactive oxygen species

RP105:

Radioprotective 105

SARM:

Sterile alpha- and armadillo-motif-containing protein

SHP:

Src homology 2 domain-containing protein tyrosine phosphatase

SIGIRR:

Single immunoglobulin IL-1R-related molecule

SNP:

Single nucleotide polymorphism

SOCS1:

Suppressor of cytokine signaling-1

ST2L:

Transmembrane form of ST2

sTLR4:

Soluble decoy TLR4

TAK:

Transforming growth factor-β-activated kinase

TANK:

TRAF family member associated NF-κB activator

TBK:

TANK binding kinase

TGF:

Transforming growth factor

TIRAP:

Toll/IL-1 receptor domain-containing adaptor protein

TNF:

Tumor necrosis factor

TIR:

Toll/interleukin 1 receptor

Tollip:

Toll interacting protein

TLR:

Toll-like receptor

TRAF:

Tumor necrosis receptor-associated factor

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

TRAM:

TRIF-related adaptor molecule

TRIAD3A:

Triad domain-containing protein 3 variant A

TRIF:

Toll/IL-1 receptor domain-containing adaptor inducing interferon-β

VCAM:

Vascular cell adhesion molecule

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  1. Serviço de Fisiologia da Faculdade de Medicina do Porto, Al. Prof. Hernâni Monteiro, 4200-319, Porto, Portugal

    João-Bruno Soares, Pedro Pimentel-Nunes, Roberto Roncon-Albuquerque Jr & Adelino Leite-Moreira

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  1. João-Bruno Soares
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  2. Pedro Pimentel-Nunes
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Soares, JB., Pimentel-Nunes, P., Roncon-Albuquerque, R. et al. The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases. Hepatol Int 4, 659–672 (2010). https://doi.org/10.1007/s12072-010-9219-x

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