PECAM‐1 modulates liver damage induced by synergistic effects of TNF‐α and irradiation

The mechanisms of radiation‐induced liver damage are poorly understood. We investigated if tumour necrosis factor (TNF)‐α acts synergistically with irradiation, and how its activity is influenced by platelet endothelial cell adhesion molecule‐1 (PECAM‐1). We studied murine models of selective single‐dose (25 Gy) liver irradiation with and without TNF‐α application (2 μg/mouse; i.p.). In serum of wild‐type (wt)‐mice, irradiation induced a mild increase in hepatic damage marker aspartate aminotransferase (AST) in comparison to sham‐irradiated controls. AST levels further increased in mice treated with both irradiation and TNF‐α. Accordingly, elevated numbers of leucocytes and increased expression of the macrophage marker CD68 were observed in the liver of these mice. In parallel to hepatic damage, a consecutive decrease in expression of hepatic PECAM‐1 was found in mice that received radiation or TNF‐α treatment alone. The combination of radiation and TNF‐α induced an additional significant decline of PECAM‐1. Furthermore, increased expression of hepatic lipocalin‐2 (LCN‐2), a hepatoprotective protein, was detected at mRNA and protein levels after irradiation or TNF‐α treatment alone and the combination of both. Signal transducer and activator of transcription‐3 (STAT‐3) seems to be involved in the signalling cascade. To study the involvement of PECAM‐1 in hepatic damage more deeply, the liver of both wt‐ and PECAM‐1‐knock‐out‐mice were selectively irradiated (25 Gy). Thereby, ko‐mice showed higher liver damage as revealed by elevated AST levels, but also increased hepatoprotective LCN‐2 expression. Our studies show that TNF‐α has a pivotal role in radiation‐induced hepatic damage. It acts in concert with irradiation and its activity is modulated by PECAM‐1, which mediates pro‐ and anti‐inflammatory signalling.