Hepatic activation of IKK/NFκB signaling induces liver fibrosis via macrophage-mediated chronic inflammation

Sunami, Yoshiaki; Leithäuser, Frank; Gul, Sarah; Fiedler, Katja; Güldiken, Nurdan; Espenlaub, Sigrid; Holzmann, Karlheinz; Hipp, Nora; Sindrilaru, Anca; Luedde, Tom; Baumann, Bernd; Wissel, Sebastian; Kreppel, Florian; Schneider, Marion; Scharffetter‐­Kochanek, Karin; Kochanek, Stefan; Strnad, Pavel; Wirth, Thomas

doi:10.1002/hep.25711

Cited by 118 publications

(110 citation statements)

References 38 publications

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“…We therefore inferred that PI3K/Akt/NF-B signaling could contribute to the progression of MesoMT, a possibility further supported by prior reports linking these pathways to mesenchymal transition in alternative cell types (10,15,18). In this study we show for the first time both PI3K/Akt and NF-B signaling are activated by thrombin and plasmin in HPMCs undergoing MesoMT.…”

supporting

confidence: 87%

Mesomesenchymal transition of pleural mesothelial cells is PI3K and NF-κB dependent

Owens

Jeffers

Boren

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pleural organization follows acute injury and is characterized by pleural fibrosis, which may involve the visceral and parietal pleural surfaces. This process affects patients with complicated parapneumonic pleural effusions, empyema, and other pleural diseases prone to pleural fibrosis and loculation. Pleural mesothelial cells (PMCs) undergo a process called mesothelial mesenchymal transition (MesoMT), by which PMCs acquire a profibrotic phenotype characterized by cellular enlargement and elongation, increased expression of α-smooth muscle actin (α-SMA), and matrix proteins including collagen-1. Although MesoMT contributes to pleural fibrosis and lung restriction in mice with carbon black/bleomycin-induced pleural injury and procoagulants and fibrinolytic proteases strongly induce MesoMT in vitro, the mechanism by which this transition occurs remains unclear. We found that thrombin and plasmin potently induce MesoMT in vitro as does TGF-β. Furthermore, these mediators of MesoMT activate phosphatidylinositol-3-kinase (PI3K)/Akt and NF-κB signaling pathways. Inhibition of PI3K/Akt signaling prevented TGF-β-, thrombin-, and plasmin-mediated induction of the MesoMT phenotype exhibited by primary human PMCs. Similar effects were demonstrated through blockade of the NF-κB signaling cascade using two distinctly different NF-κB inhibitors, SN50 and Bay-11 7085. Conversely, expression of constitutively active Akt-induced mesenchymal transition in human PMCs whereas the process was blocked by PX866 and AKT8. Furthermore, thrombin-mediated MesoMT is dependent on PAR-1 expression, which is linked to PI3K/Akt signaling downstream. These are the first studies to demonstrate that PI3K/Akt and/or NF-κB signaling is critical for induction of MesoMT.

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supporting

confidence: 87%

Mesomesenchymal transition of pleural mesothelial cells is PI3K and NF-κB dependent

Owens

Jeffers

Boren

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…CCL5 expression is known to be regulated by transcription factors, including NF-B (26). In addition, a previous study provided an important link between hepatocyte NF-B activation and liver fibrosis development (38). Furthermore, a very recent report demonstrated an important role of hepatocyte Toll-like receptor 4 (TLR4) in obesity-induced inflammation in mice (16).…”

Section: Discussionmentioning

confidence: 99%

Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice

Kizu

Yoshida

Furuta

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Grb2-associated binder 1 (Gab1) adaptor protein amplifies signals downstream of a broad range of growth factors/receptor tyrosine kinases. Although these signals are implicated in liver fibrogenesis, the role of Gab1 remains unclear. To elucidate the role of Gab1, liver fibrosis was examined in hepatocyte-specific Gab1-conditional knockout (Gab1CKO) mice upon bile duct ligation (BDL). Gab1CKO mice developed exacerbated liver fibrosis with activation of hepatic myofibroblasts after BDL compared with control mice. The antifibrotic role of hepatocyte Gab1 was further confirmed by another well-established mouse model of liver fibrosis using chronic injections of carbon tetrachloride. After BDL, Gab1CKO mice also displayed exacerbated liver injury, decreased hepatocyte proliferation, and enhanced liver inflammation. Furthermore, cDNA microarray analysis was used to investigate the potential molecular mechanisms of the Gab1-mediated signal in liver fibrosis, and the fibrosis-promoting factor chemokine (C-C motif) ligand 5 ( Ccl5) was identified as upregulated in the livers of Gab1CKO mice following BDL. Interestingly, in vitro studies using primary hepatocytes isolated from control and Gab1CKO mice revealed that the loss of Gab1 resulted in increased hepatocyte CCL5 synthesis upon lipopolysaccharide stimulation. Finally, pharmacological antagonism of CCL5 reduced BDL-induced liver fibrosis in Gab1CKO mice. In conclusion, our results demonstrate that hepatocyte Gab1 is required for liver fibrosis and that hepatocyte CCL5 could be an important contributor to this process. Thus, we present a novel antifibrotic function of hepatocyte Gab1 in liver fibrogenesis.

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“…The RelA signalling pathway is associated with the pathogenesis of fibrosis including organs such as kidney, liver and lung 5, 6, 7, 8, 9, 10, 11, 12, 13. In unstimulated cells, the cytoplasmic NF‐κB is bound to the inhibitory protein IκB; the complex prevents NF‐κB activation ( i.e .…”

Section: Introductionmentioning

confidence: 99%

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

Mia

Bank

2015

J Cellular Molecular Medi

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Excessive accumulation of a collagen‐rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGFβ1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF‐κB) pathway by phosphorylating IκB with the enzyme IκB kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2‐Amino‐6‐[2‐(cyclopropylmethoxy)‐6‐hydroxyphenyl]‐4‐(4‐piperidinyl)‐3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activation of the NF‐κB pathway. It is not known whether ACHP has potential anti‐fibrotic properties. Using adult human dermal and lung fibroblasts we have investigated whether ACHP has the ability to inhibit the TGFβ1‐induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The presence of ACHP strongly suppressed the induction of the myofibroblast markers alpha‐smooth muscle actin (αSMA) and SM22α, as well as the deposition of the ECM components collagen type I and fibronectin. Furthermore, post‐treatment with ACHP partly reversed the expression of αSMA and collagen type I production. Finally, ACHP suppressed the expression of the three collagen‐modifying enzymes lysyl hydroxylase (PLOD1,PLOD2 and PLOD3) in dermal fibroblasts, but did not do so in lung fibroblasts. We conclude that the IKK inhibitor ACHP has potent antifibrotic properties, and that the NF‐κB pathway plays an important role in myofibroblast biology.

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Hepatic activation of IKK/NFκB signaling induces liver fibrosis via macrophage-mediated chronic inflammation

Cited by 118 publications

References 38 publications

Mesomesenchymal transition of pleural mesothelial cells is PI3K and NF-κB dependent

Mesomesenchymal transition of pleural mesothelial cells is PI3K and NF-κB dependent

Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

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