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Histological Analyses of Acute Alcoholic Liver Injury in Zebrafish
Published on: May 25, 2017
Liver kinome reveals PS1145 as therapeutic agent for mitigating systemic inflammation in alcohol-related liver
Manisha Yadav1, Abhishak Gupta2, Sanju Yadav1
1Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
Rationale:
Alcohol-related liver disease (ALD) lacks effective anti-inflammatory therapies, and since kinases orchestrate inflammation, kinome profiling offers a rational approach to identify and validate novel therapeutic targets.
Objective:
To analyse liver and monocyte kinome alterations in a chronic ethanol-fed pre-clinical rat model and identify therapeutic targets capable of mitigating inflammation. Pathway-specific inhibitors, including PS1145 (IKK-phosphorylation-inhibitor), PH797804 (MAPK14-inhibitor), resveratrol, and prednisolone were evaluated in ALD-rats, PBMCs from patients, and the NIAAA mouse model.
Findings:
Kinome profiling identified 497 hepatic and 345 monocyte kinases in ALD rats (FDR<0.01), with a time-dependent increase in MAPK14-associated kinases in both tissues (FC>1.5, p < 0.05). By 24 weeks, 172-liver and 48-monocyte kinases were upregulated, primarily involving MyD88-TLR4, PI3K-Akt, TNF, TGFβ-TGFβR1, senescence and ROS-generating kinases and IL-1-driven MAPK14 and IKK phosphorylation(p < 0.05). Targeting this axis, PS1145 suppressed NFκB activation and inflammation in THP1, HepG2 cells, PBMCs from healthy and SAH-patients, outperforming PH797804, resveratrol, and prednisolone (FC>1.5,p < 0.05). PS1145 significantly reduced IL-6, TNFα, and NFκB, while increasing IL-10. In NIAAA-mouse model, PS1145 treatment reduced hepatic steatosis, cellular stress, and inflammation, IL36R disrupting TLR dimerization more effectively than standard therapies (p < 0.05).
Conclusion:
PS1145 blocks IKK phosphorylation and TLR dimerization, attenuating inflammation and improving liver pathology, highlighting its therapeutic potential in ALD.
Insights
PS1145, an IKK-phosphorylation inhibitor, effectively reduces inflammation and liver damage in alcohol-related liver disease (ALD) models. It targets key inflammatory pathways, showing therapeutic promise where other treatments fall short.
Area of Science:
- Hepatology
- Immunology
- Pharmacology
Background:
- Alcohol-related liver disease (ALD) lacks effective anti-inflammatory treatments.
- Kinase signaling pathways are crucial in orchestrating inflammatory responses.
- Kinome profiling is a rational approach to identify novel therapeutic targets for ALD.
Purpose of the Study:
- To analyze liver and monocyte kinome alterations in a chronic ethanol-fed rat model.
- To identify therapeutic targets for mitigating inflammation in ALD.
- To evaluate pathway-specific inhibitors, including PS1145, in preclinical ALD models.
Main Methods:
- Kinome profiling in liver and monocytes of chronic ethanol-fed rats.
- Evaluation of inhibitors (PS1145, PH797804, resveratrol, prednisolone) in ALD rats, patient PBMCs, and NIAAA mouse models.
- Analysis of inflammatory markers, NFκB activation, and TLR signaling.
Main Results:
- Kinome profiling revealed significant alterations in hepatic and monocyte kinases in ALD rats.
- Upregulation of kinases involved in MyD88-TLR4, PI3K-Akt, TNF, and MAPK14 pathways was observed.
- PS1145 suppressed NFκB activation and inflammation, outperforming other tested inhibitors, and improved liver pathology in mouse models.
Conclusions:
- PS1145 effectively blocks IKK phosphorylation and TLR dimerization.
- This inhibition attenuates inflammation and improves liver pathology in ALD.
- PS1145 demonstrates significant therapeutic potential for treating alcohol-related liver disease.
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