PECAM-1 mediated liver damage in a selective liver radiation model: a role for TNF-α

Question:

The liver is considered to be radiosensitive; however, the mechanism of radiation-induced liver damage is poorly understood. Platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31) is an adhesion molecule and expressed mainly in blood- and endothelial cells, and its expression is decreased during inflammatory processes. Tumor necrosis factor (TNF)-α is known to downregulate the PECAM-1 expression, the level of TNF-α is induced by radiation. The current study investigated if treatment of TNF-α could enhance the irradiation induced liver damage through regulating PECAM-1 signaling pathway.

Methods:

This was studied in-vivo in the mice models of single-dose selective liver irradiation, in the presence or absence of TNF-α which was administered intraperitoneally short before irradiation.

Results:

Irradiation exhibited mild AST-level elevation (hepatic damage) in mice serum, compared to sham-irradiated mice. This elevation was further enhanced in mice, which received TNF-α alone or combined treatment of irradiation and TNF-α. In correspondence an increase number of leukocytes was observed in mice liver after TNF-α or TNF-α and irradiation treatment compared to irradiation alone. The levels of AST or number of migrated cells into the liver were higher in mice, which received TNF-α and irradiation together compared to irradiation or TNF-α alone. In parallel to hepatic damage, a time dependent decrease in the gene expression of hepatic PECAM-1 was found in mice that received radiation or TNF-α treatment alone. The administration of radiation together with TNF-α showed additional decline in the gene expression of PECAM-1. In contrast, an increased expression of hepatic lipocalin- 2 (LCN-2), an acute phase protein, was detected at mRNA and protein level after irradiation or TNF-α treatment alone, compared to sham-irradiated mice. The level of LCN-2 was further increased in mice treated with TNF-α and radiation together, compared to irradiation or TNF-α alone. This induction could be mediated by the activation of STAT-3 pathway. In order to study the role of PECAM-1 in hepatic damage, the liver of both wild-type (wt) and knock-out (ko)-mice were selectively irradiated (25 Gy). PECAM-1-ko-mice showed higher liver damage in parallel to increased LCN-2 gene expression compared to wt-mice at RNA and protein level.

Conclusions:

Our study showed that the synergistic effect of radiation and TNF-α could enhance hepatic cell-damage through regulation of PECAM-1. Our result could help to develop protective agents to reduce radiation-induced consequences in normal tissue, and the agents which could increase the effect of radiation on tumor tissue.