Diammonium Glycyrrhizinate Mitigates Liver Injury Via Inhibiting Proliferation Of NKT Cells And Promoting Proliferation Of Tregs

  • Drug Des Devel Ther. 2019 Oct 16:13:3579-3589. doi: 10.2147/DDDT.S220030.
Meixin Gao  #  1 ,  Xiulan Li  #  2 ,  Lingling He  3 ,  Junru Yang  3 ,  Xiaohui Ye  3 ,  Fan Xiao  4 ,  Hongshan Wei  1  2  3
Affiliations
  • 1. Department of Gastroenterology, Peking University Ditan Teaching Hospital, Beijing 100015, People's Republic of China.
  • 2. Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, People's Republic of China.
  • 3. Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, People's Republic of China.
  • 4. Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, People's Republic of China.
  • # Contributed equally.
PMID: 31802846 DOI: 10.2147/DDDT.S220030
Abstract

Purpose: Diammonium glycyrrhizinate (DG) is a replacement for glycyrrhizic acid, which is used as a hepatic protector in clinical practice for most liver diseases. The potential role of immune response during autoimmune hepatitis-induced by concanavalin A (Con A)-remains to be elucidated.

Methods: C57BL/6J mice were treated with two different doses of DG (75 and 200 mg/kg) 2 hrs before administering Con A. The mice were sacrificed after administering Con A for 0, 6, and 24 hrs. Liver damage grade and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin levels were evaluated. The expression level of cleaved-caspase 3 in liver was detected by Western blotting. Inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interferon γ (IFN-γ) in liver were detected by RT-PCR. Thymus, peripheral blood, spleen, and liver tissues were collected to analyze the percentages of NKT cells, subsets of CD4+CD25-CD69+ and CD8+CD69+ T cells, and subsets of regulatory T cells (Tregs).

Results: Our results revealed that DG pre-treatment significantly decreased the serum ALT and AST levels and improved the histological damage in Con A-induced autoimmune liver injury. Pre-treatment with DG down-regulated the inflammatory cytokines upon challenge with Con A. The DG pre-treatment inhibited the Apoptosis of T lymphocytes in the thymus. Further, it effectively suppressed the proliferation of CD4+CD25-CD69+ and CD8+CD69+ subsets in the peripheral blood and spleen. In addition, the DG pretreatment significantly downregulated the frequency of NKT cells, while upregulating the frequency of Tregs in the liver.

Conclusion: We believe that the potential protective effect of DG against Con A-induced hepatitis may be partially attributed to its inhibitory activities on inflammatory cytokines in the livers, lymphocyte Apoptosis in the thymus, NKT cells proliferation, and activation of CD8+T cells; further, there may also be a possibility of DC promoting Tregs proliferation.

Keywords
NKT cells; autoimmune hepatitis; concanavalin A; diammonium glycyrrhizinate; regulatory T-cell.
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