1. Academic Validation
  2. Adenosine receptor A2B mediates alcoholic hepatitis by regulating cAMP levels and the NF-KB pathway

Adenosine receptor A2B mediates alcoholic hepatitis by regulating cAMP levels and the NF-KB pathway

  • Toxicol Lett. 2022 Apr 15;359:84-95. doi: 10.1016/j.toxlet.2022.01.012.
Ning Zhao 1 Guoqing Xia 1 Junnan Cai 1 ZiXuan Li 1 Xiong-Wen Lv 2
Affiliations

Affiliations

  • 1 Institute for Liver Diseases of Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China.
  • 2 Institute for Liver Diseases of Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China. Electronic address: lyuxw@ahmu.edu.cn.
Abstract

Alcoholic hepatitis is a serious form of liver damage. Inflammation is a key factor in alcoholic hepatitis and plays a key role in the progression of alcoholic liver disease. Adenosine Receptor A2B (A2BAR) is a member of the Adenosine Receptor family and generally considered to be a negative regulator of the inflammatory response. We found that A2BAR was the most highly expressed Adenosine Receptor in ETOH-fed mouse liver tissue and was also highly expressed in primary Kupffer cells and ETOH-induced RAW264.7 cells. In addition, injection of BAY 60-6583 stimulated A2BAR, induced upregulation of the expression levels of cAMP, and reduced ETOH-induced steatosis and inflammation in mice. At the same time, knockdown of A2BAR in vitro increased the inflammatory response in RAW264.7 cells triggered by ETOH. After knockdown of A2BAR in vitro, the release of the inflammatory cytokines IL-6, IL-1β and TNF-α was increased. After overexpression of A2BAR in vitro, the cAMP level was significantly increased, PKA expression was increased, the expression of phosphorylated proteins in the NF-kB signal transduction pathway was significantly affected, and the expression of the key phosphorylated protein p-P65 was decreased. However, after the simultaneous overexpression of A2BAR and inhibition of PKA, the expression of the key phosphorylated protein p-P65 was still significantly decreased. In addition, after the expression of A2BAR increased or decreased in RAW264.7 cells, AML-12 cells were cultured in the supernatant of RAW264.7 cells stimulated by ETOH, and the Apoptosis rate was significantly changed by flow cytometry. These results suggest that A2BAR can reduce alcoholic steatohepatitis by upregulating cAMP levels and negatively regulating the NF-kB pathway. Overall, these findings suggest the significance of A2BAR-mediated inflammation in alcoholic liver disease.

Keywords

A2BAR; AML-12; ASH; Inflammation; Macrophage; cAMP.

Figures
Products