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Toll-like receptor signaling and liver fibrosis.

Aoyama T, Paik YH, Seki E - Gastroenterol Res Pract (2010)

Bottom Line: Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host.The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine.Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive MC# 0702, Leichtag Biomedical Research Building Rm# 332 MM, La Jolla, CA 92093-0702, USA.

ABSTRACT
Liver fibrosis occurs as a wound-healing scar response following acute and chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis B and C, and autoimmune hepatitis. Myofibroblasts, mainly transdifferentiated from hepatic stellate cells, are pivotal cell types that produce fibrillar collagen. The activation of inflammatory cells, including Kupffer cells, is a crucial step for activating hepatic stellate cells. Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes in the liver. TLR signaling induces potent innate immune responses in these cell types. The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine. Recent evidence demonstrates the role of TLRs in the activation of hepatic immune cells and stellate cells during liver fibrosis. Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported. This paper highlights the role of TLR signaling in stellate cell activation and the progression of liver fibrosis.

No MeSH data available.


Related in: MedlinePlus

Ablation of TAK1 in hepatocytes induces spontaneous liver injury, inflammation, fibrosis, and cancer. Spontaneous hepatocyte death occurs in hepatocyte specific TAK1-deficient mice followed by the release of damage-associated molecular patterns (DAMPs) which stimulate Kupffer cells to produce TNF-α. This TNF-α further induces cell death in TAK1-deficient hepatocytes lacking activation of NF-κB and JNK. TNF-α, IL-1β, and IL-6 released from Kupffer cells cause liver inflammation. Kupffer cell-derived TGF-β stimulates hepatic stellate cells resulting in fibrogenesis. The persistent hepatocyte death and uncontrolled compensatory proliferation in the livers of hepatocyte specific TAK1-deficient mice induce the reactivation of onco-fetal liver genes that are associated with the initiation of hepatic carcinogenesis.
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fig2: Ablation of TAK1 in hepatocytes induces spontaneous liver injury, inflammation, fibrosis, and cancer. Spontaneous hepatocyte death occurs in hepatocyte specific TAK1-deficient mice followed by the release of damage-associated molecular patterns (DAMPs) which stimulate Kupffer cells to produce TNF-α. This TNF-α further induces cell death in TAK1-deficient hepatocytes lacking activation of NF-κB and JNK. TNF-α, IL-1β, and IL-6 released from Kupffer cells cause liver inflammation. Kupffer cell-derived TGF-β stimulates hepatic stellate cells resulting in fibrogenesis. The persistent hepatocyte death and uncontrolled compensatory proliferation in the livers of hepatocyte specific TAK1-deficient mice induce the reactivation of onco-fetal liver genes that are associated with the initiation of hepatic carcinogenesis.

Mentions: TAK1 is a MAP3K which is activated by the signaling of TLRs, IL-1 receptor, TNF receptor, and TGF-β receptor [43, 44]. TAK1 is an upstream kinase of both IKK/NF-κB and JNK/AP-1 pathways [15]. The NF-κB pathway regulates the expression of antiapoptotic genes, such as Bcl-2, Bcl-xL, A20, iNOS, c-FLIP, IAPs, and TRAF family molecules, to block death receptor-mediated or mitochondria-mediated hepatocytes death [45]. NF-κB also prevents prolonged JNK activation. Prolonged JNK activation induces phosphorylation of the E3 ligase Itch and subsequent ubiquitination and degradation of caspase-8 inhibitor c-FLIP, which accelerates hepatocyte apoptosis [46]. Thus, NF-κB protects hepatocytes from apoptosis whereas JNK promotes apoptosis. Therefore, we could not predict whether TAK1 tends to induce or protect from hepatocyte apoptosis. As expected, neither NF-κB nor JNK activation following TNF-α stimulation occurred in TAK1−/− hepatocytes [47]. Surprisingly, TAK1−/− hepatocytes increased the sensitivity to TNF-α-induced cell death. More surprisingly, spontaneous hepatocyte death occurred in hepatocyte specific TAK1−/− mice [47]. These mice display spontaneous liver injury, inflammation, and fibrosis at the age of one month and develop hepatocellular carcinoma at the age of nine months [47, 48]. These results suggest that spontaneous persistent hepatocyte death occurs in hepatocyte specific TAK1−/− mice, and these dying hepatocytes release alarmins which stimulate both Kupffer cells and HSCs, resulting in liver inflammation and fibrosis Figure 2. These findings are evidence that liver fibrosis and carcinogenesis are associated with persistent hepatocyte injury and inflammation without any carcinogens. Hepatocyte specific TAK1−/− mice will be great animal models for addressing the role of the interplay between fibrosis and hepatocellular carcinoma.


Toll-like receptor signaling and liver fibrosis.

Aoyama T, Paik YH, Seki E - Gastroenterol Res Pract (2010)

Ablation of TAK1 in hepatocytes induces spontaneous liver injury, inflammation, fibrosis, and cancer. Spontaneous hepatocyte death occurs in hepatocyte specific TAK1-deficient mice followed by the release of damage-associated molecular patterns (DAMPs) which stimulate Kupffer cells to produce TNF-α. This TNF-α further induces cell death in TAK1-deficient hepatocytes lacking activation of NF-κB and JNK. TNF-α, IL-1β, and IL-6 released from Kupffer cells cause liver inflammation. Kupffer cell-derived TGF-β stimulates hepatic stellate cells resulting in fibrogenesis. The persistent hepatocyte death and uncontrolled compensatory proliferation in the livers of hepatocyte specific TAK1-deficient mice induce the reactivation of onco-fetal liver genes that are associated with the initiation of hepatic carcinogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2913673&req=5

fig2: Ablation of TAK1 in hepatocytes induces spontaneous liver injury, inflammation, fibrosis, and cancer. Spontaneous hepatocyte death occurs in hepatocyte specific TAK1-deficient mice followed by the release of damage-associated molecular patterns (DAMPs) which stimulate Kupffer cells to produce TNF-α. This TNF-α further induces cell death in TAK1-deficient hepatocytes lacking activation of NF-κB and JNK. TNF-α, IL-1β, and IL-6 released from Kupffer cells cause liver inflammation. Kupffer cell-derived TGF-β stimulates hepatic stellate cells resulting in fibrogenesis. The persistent hepatocyte death and uncontrolled compensatory proliferation in the livers of hepatocyte specific TAK1-deficient mice induce the reactivation of onco-fetal liver genes that are associated with the initiation of hepatic carcinogenesis.
Mentions: TAK1 is a MAP3K which is activated by the signaling of TLRs, IL-1 receptor, TNF receptor, and TGF-β receptor [43, 44]. TAK1 is an upstream kinase of both IKK/NF-κB and JNK/AP-1 pathways [15]. The NF-κB pathway regulates the expression of antiapoptotic genes, such as Bcl-2, Bcl-xL, A20, iNOS, c-FLIP, IAPs, and TRAF family molecules, to block death receptor-mediated or mitochondria-mediated hepatocytes death [45]. NF-κB also prevents prolonged JNK activation. Prolonged JNK activation induces phosphorylation of the E3 ligase Itch and subsequent ubiquitination and degradation of caspase-8 inhibitor c-FLIP, which accelerates hepatocyte apoptosis [46]. Thus, NF-κB protects hepatocytes from apoptosis whereas JNK promotes apoptosis. Therefore, we could not predict whether TAK1 tends to induce or protect from hepatocyte apoptosis. As expected, neither NF-κB nor JNK activation following TNF-α stimulation occurred in TAK1−/− hepatocytes [47]. Surprisingly, TAK1−/− hepatocytes increased the sensitivity to TNF-α-induced cell death. More surprisingly, spontaneous hepatocyte death occurred in hepatocyte specific TAK1−/− mice [47]. These mice display spontaneous liver injury, inflammation, and fibrosis at the age of one month and develop hepatocellular carcinoma at the age of nine months [47, 48]. These results suggest that spontaneous persistent hepatocyte death occurs in hepatocyte specific TAK1−/− mice, and these dying hepatocytes release alarmins which stimulate both Kupffer cells and HSCs, resulting in liver inflammation and fibrosis Figure 2. These findings are evidence that liver fibrosis and carcinogenesis are associated with persistent hepatocyte injury and inflammation without any carcinogens. Hepatocyte specific TAK1−/− mice will be great animal models for addressing the role of the interplay between fibrosis and hepatocellular carcinoma.

Bottom Line: Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host.The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine.Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive MC# 0702, Leichtag Biomedical Research Building Rm# 332 MM, La Jolla, CA 92093-0702, USA.

ABSTRACT
Liver fibrosis occurs as a wound-healing scar response following acute and chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis B and C, and autoimmune hepatitis. Myofibroblasts, mainly transdifferentiated from hepatic stellate cells, are pivotal cell types that produce fibrillar collagen. The activation of inflammatory cells, including Kupffer cells, is a crucial step for activating hepatic stellate cells. Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes in the liver. TLR signaling induces potent innate immune responses in these cell types. The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine. Recent evidence demonstrates the role of TLRs in the activation of hepatic immune cells and stellate cells during liver fibrosis. Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported. This paper highlights the role of TLR signaling in stellate cell activation and the progression of liver fibrosis.

No MeSH data available.


Related in: MedlinePlus