The contribution of toll‐like receptor signaling to the development of liver fibrosis and cancer in hepatocyte‐specific TAK1‐deleted mice

Abstract

Hepatocyte death is associated with liver inflammation, fibrosis and hepatocellular carcinoma (HCC). Damaged cells trigger inflammation through activation of Toll-like receptors (TLRs). Although the role of TLR4 in HCC development has been reported, the role of TLR9 in the development of HCC remains elusive. To investigate the role of TLR4 and TLR9 signaling in liver inflammation-fibrosis-cancer axis, we took advantage of mice with hepatic deletion of transforming growth factor-β- activated kinase 1 (Tak1ΔHep) that develop spontaneous liver injury, inflammation, fibrosis, and HCC, recapitulating the pathology of human HCC. We generated double knockout mice lacking genes of our interest with hepatic Tak1. Tak1ΔHep mice and Tlr4-deficient Tak1ΔHep mice had similar serum ALT levels, but Tlr4-deficient Tak1ΔHep mice exhibited significantly reduced macrophage infiltration, myofibroblast activation and tumor formation. Ablation of TLR9 reduced spontaneous liver injury, inflammation, fibrosis, and cancer development in Tak1ΔHep mice. In addition, the common adaptor, myeloid differentiation factor 88 (MyD88)-deficient Tak1ΔHep mice also attenuated liver injury, macrophage recruitment, collagen deposition, and tumor growth compared with control Tak1ΔHep mice. Genetic ablation of TNF receptor type I (TNFR) in Tak1ΔHep mice remarkably reduced liver inflammation-fibrosis-cancer axis. Surprisingly, disruption of interleukin-1 receptor (IL-1R) had no effect on liver injury and tumor formation, although Il1r-deficient Tak1ΔHep showed attenuated macrophage infiltration and collagen deposition. In conclusion, TLR4- and TLR9-MyD88 are driving forces of progression to HCC accompanied by liver inflammation and fibrosis in Tak1ΔHep mice. Importantly, TLR4 and TLR9 downstream TNFR, but not IL-1R signaling is crucial for the development of HCC in Tak1ΔHep mice.

Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets

“…13,14 In experiments with TNF receptor type I (TNFRI) À/À mice, TNFRI knockout did not reduce diethylnitrosamine (DEN)-induced HCC, but did suppress high-fat diet (HFD)-promoted DEN-induced HCC, lymphotoxin α/β À overexpression-induced HCC, and hepatocyte-specific transforming growth factor beta-activated kinase 1 (TAK1)deletion-induced HCC. [15][16][17] NF-κB has dual functions in hepatocarcinogenesis. NF-κB-induced inflammation is known to promote tumorigenesis.…”

“…TLR4 knockout reduced the HCC burden compared with control mice in a DEN plus CCl 4 fibrosis-associated HCC mouse model and in TAK1 Δhep mice and PTEN Δhep mice. 17,45,46 HCC burden reduced when gut-derived LPS was depleted by orally administering nonabsorbable antibiotics in the DEN plus CCl 4 model and in PTEN Δhep mice. 45,46 Continuous low-dose administration of LPS enhanced HCC development, whereas germ-free conditions decreased it.…”

“…45 The DEN plus CCl 4 model did not show that TLR9 contributes to HCC development; 48 however, TLR9 plays a significant role in HCC development in TAK1 Δhep mice and hypoxia-mediated HCC growth. 17,49,50 This finding is unsurprising given the diverse mechanisms of HCC development in humans. Accordingly, different mouse HCC models should have similarly diverse and distinct molecular mechanisms.…”

Immunologia dla specjalistów medycyny paliatywnej. Rola receptorów Toll-like w wywoływaniu objawów choroby

“…In addition to depression, the relationship between the neurogenic inflammation and the development of medical condition was described with regard to Parkinson's disease [21,22], multiple system atrophy [21],dementia [23], Guillian-Barré syndrome [24], multiple sclerosis [25], and other atrophic diseases of the nervous system. The passive immunity system was associated with the growth of tumours, inter alia, of reproductive organs in women [26], of large intestine [27], lungs [28] and liver [29].…”

“…Oprócz depresji, związek pomiędzy zapaleniem neurogennym a rozwojem schorzenia opisano dla choroby Parkinsona [21,22], zespołu atrofii wielonarządowej [21], otępienia [23], zespołu Guillian-Barré [24], stwardnienia rozsianego [25] i innych chorób zanikowych układu nerwowego. System odporności biernej powiązano ze wzrostem nowotworów, między innymi narządu rodnego u kobiet [26], jelita grubego [27], płuca [28] i wątroby [29].…”