Adhesion molecules and liver inflammation after radiation: Role of PECAM-1.

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The role of PECAM-1 (CD31) and CD99L2 in inflammation is still under debate. It is hypothesized that in inflammatory conditions, PECAM-1- (and possibly CD99L2)- down-regulation in parallel to ICAM-1-up-regulation is induced by TNF- through upregulation of NF-kB and downregulation of JNK allowing inflammatory cells to attach to and to transmigrate through the vessel wall (portal area). In contrast, TGF- could stop this process and/or help in repair. Effect of radiation on PECAM-1- and CD99L2- regulation will be studied after TNF- or TGF- administration in wild type mice and in PECAM-1-ko-mice. Immunohistology of liver sections, gene expression of cytokine- and target genes (PECAM-1, ICAM-1 and CD99L2) at mRNA and protein level will be performed. Furthermore, Laser capture microdissection (LCM) of liver sections will be used to measure amount of mRNA (PECAM-1, ICAM-1 and CD99L2) in the different areas of the liver lobule. Flow-cytometry analysis will be used to quantify PECAM-1, ICAM-1 and CD99L2 level on isolated liver and inflammatory cells. Gene expression will also be studied at RNA- (PCR, gene array) and protein level (Western blot) from sorted cell populations (by MACS-separator). Effect of TNF- and/or TGF- will be investigated in transmigration studies (granulocytes, macrophages) on cultured endothelial cells. The new knowledge will help to find therapeutic means to reduce radiation induced damage and fibrosis in the liver.