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Lymphocyte-Specific Protein Tyrosine Kinase Contributes to Spontaneous Regression of Liver Fibrosis may by Interacting with Suppressor of Cytokine Signaling 1

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Abstract

Quiescent hepatic stellate cells (qHSCs), converted to myofibroblasts, produce fibrous scars, which is an essential event during liver fibrogenesis. Clinical and experimental fibrosis undergo remarkable regression when the underlying etiological agent is removed. Some myofibroblasts revert to an inactive phenotype (iHSCs) during the regression of fibrosis. However, the mechanisms underlying HSC activation and reversal remain unclear. The present study demonstrated that the expression of lymphocyte-specific protein tyrosine kinase (LCK) was increased in fibrotic livers but decreased after spontaneous recovery in vivo and in vitro, which was correlated with the expression of α-smooth muscle actin (α-SMA) and type I collagen (COL-1). Further investigation indicated that specific knockdown of LCK by a recombination adeno-associated virus 9 (rAAV9) in C57BL/6 mice ameliorated liver fibrosis. Co-incubation of TGF-β1-induced HSC-T6 cells with LCK-siRNA inhibited cell proliferation and activation. Overexpression of LCK inhibited activated HSCs going to inactivated phenotype. Interestingly, we found that LCK may interact with suppressor of cytokine signaling 1 (SOCS1) and may influence the expression of p-JAK1 and p-STAT1/3. These data suggest that LCK may play a regulatory role in liver fibrosis by inhibiting SOCS1, indicating that LCK is a potential therapeutic target for liver fibrosis treatment.

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Abbreviations

rAAV9:

Recombination adeno-associated viruses

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

α-SMA:

α-Smooth muscle actin

CCl4 :

Carbon tetrachloride

COl1α1:

Type I collagen

ECM:

Extracellular matrix

HA:

Hyaluronic acid

HSC:

Hepatic stellate cell

JAK1:

Janus kinase-1

LCK:

Lymphocyte-specific protein tyrosine kinase

LN:

Laminin

PCIII:

Type 3 procollagen

siRNA:

Small interfering RNA

SOCS1:

Suppressor of cytokine signaling 1

STAT1:

Signal transducer and activator of transcription 1

STAT3:

Signal transducer and activator of transcription 3.

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Acknowledgements

The authors thank the Center for Scientific Research of Anhui Medical University for valuable help in our experiment. This work was supported by funding from the National Science Foundation of China (82070628) and the University Synergy Innovation Program of Anhui Province (GXXT-2019-045, GXXT-2020-063, GXXT-2020-025). The authors thank the Center for Scientific Research of Anhui Medical University for valuable help in our experiment.

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  1. Huizi Zhao and Hong Zhu contributed equally to this work.

Authors and Affiliations

  1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China

    Huizi Zhao, Hong Zhu, Yuan Zhang, Yuhao Ding, Rui Feng, Jun Li, Taotao Ma & Cheng Huang

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  1. Huizi Zhao
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Huizi Zhao and Hong Zhu wrote the manuscript text. Yuan Zhang and Yuhao Ding prepared figures and collected samples. Rui Feng, Jun Li, Taotao Ma, and Cheng Huang designed the experiment.

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Correspondence to Taotao Ma or Cheng Huang.

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Zhao, H., Zhu, H., Zhang, Y. et al. Lymphocyte-Specific Protein Tyrosine Kinase Contributes to Spontaneous Regression of Liver Fibrosis may by Interacting with Suppressor of Cytokine Signaling 1. Inflammation 46, 1653–1669 (2023). https://doi.org/10.1007/s10753-023-01831-4

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