Hepatoma-derived growth factor participates in concanavalin A-induced hepatitis.

Abstract

Hepatitis is an important health problem worldwide. Novel molecular targets are in demand for detection and management of hepatitis. Hepatoma-derived growth factor (HDGF) has been delineated to participate in hepatic fibrosis and liver carcinogenesis. However, the relationship between hepatitis and HDGF remains unclear. This study aimed to elucidate the role of HDGF during hepatitis using concanavalin A (ConA)-induced hepatitis model. In cultured hepatocytes, ConA treatment-elicited HDGF upregulation at transcriptional level and promoted HDGF secretion while reducing intracellular HDGF protein level and cellular viability. Similarly, mice receiving ConA administration exhibited reduced hepatic HDGF expression and elevated circulating HDGF level, which was positively correlated with serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. By using HDGF knockout (KO) mice, it was found the ConA-evoked cell death was prominently alleviated in KO compared with control. Besides, it was delineated HDGF ablation conferred protection by suppressing the ConA-induced neutrophils recruitment in livers. Above all, the ConA-mediated activation of tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)/interleukin-6 (IL-6)/cyclooxygenase-2 (COX-2) inflammatory signaling was significantly abrogated in KO mice. Treatment with recombinant HDGF (rHDGF) dose-dependently stimulated the expression of TNF-α/IL-1β/IL-6/COX-2 in hepatocytes, further supporting the pro-inflammatory function of HDGF. Finally, application of HDGF antibody not only attenuated the ConA-mediated inflammatory cascade in hepatocytes, but also ameliorated the ConA-induced hepatic necrosis and AST elevation in mice. In summary, HDGF participates in ConA-induced hepatitis via neutrophils recruitment and may constitute a therapeutic target for acute hepatitis.

• Authors: E-Ming Wang, Tsung-Hui Hu, Chao-Cheng Huang, Yi-Chen Chang, Shih-Ming Yang, Shih-Tsung Huang, Jian-Ching Wu, Yi-Ling Ma, Hoi-Hung Chan, Li-Feng Liu, Wen-Bin Lu, Mei-Lang Kung, Zhi-Hong Wen, Jui-Chu Wang, Chou-Yuan Ko, Wei-Lun Tsai, Tian-Huei Chu, Ming-Hong Tai
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 34 Issue 12 Pg. 16163-16178 (12 2020) ISSN: 1530-6860 [Electronic] United States
• PMID: 33063394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Federation of American Societies for Experimental Biology.

Chemical References

• Intercellular Signaling Peptides and Proteins
• Interleukin-1beta
• Interleukin-6
• Tumor Necrosis Factor-alpha
• hepatoma-derived growth factor
• Concanavalin A
• Aspartate Aminotransferases
• Alanine Transaminase

Topics

• Alanine Transaminase (metabolism)
• Animals
• Aspartate Aminotransferases (metabolism)
• Cells, Cultured
• Concanavalin A (pharmacology)
• Hepatitis, Animal (chemically induced, metabolism)
• Hepatocytes (drug effects, metabolism)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Interleukin-1beta (metabolism)
• Interleukin-6 (metabolism)
• Liver (drug effects, metabolism)
• Liver Cirrhosis (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophil Infiltration (drug effects)
• Rats
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation (drug effects)