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-1ß (IL-1ß)/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-1ß/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.