INFLUENCE OF BACTERIAL-ENDOTOXIN ON RADIATION-INDUCED ACTIVATION OF HUMAN ENDOTHELIAL-CELLS IN-VITRO AND IN-VIVO - PROTECTIVE ROLE OF IL-10

Previous work from our group has contributed to demonstrate the role o f conditioning related release of proinflammatory cytokines in inducti on of acute graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation (BMT). In the present report we show that ioni zing radiation (IR) in a clinical relevant dose upregulates intercellu lar adhesion molecule 1 (ICAM-1) on cultured human microvascular endot helial cells (HMEC). Bacterial endotoxin (lipopolysaccharide, LPS) in a concentration corresponding to serum levels seen during clinical end otoxemia, is capable of further enhancing ICAM-1 expression on irradia ted cells, Adhesion assays with freshly isolated peripheral blood mono nuclear cells (PBMC) revealed that increased ICAM-1 expression on IR-t reated endothelial cells led to an increased adhesion of PBMC, Again, this effect could be superinduced by LPS. Recombinant human interleuki n 10 (IL-10), an antagonistic cytokine known to function as an LPS ant agonist, was able to counteract the LPS-mediated enhancement of IR-tri ggered ICAM-1 induction and PBMC adhesion, In contrast, IL-10 could no t inhibit irradiation caused effects. IL-10 seemed to interfere with t he translocation of preformed intracellular ICAM-1 to the cell membran e. To investigate whether this superinductive function of IR and LPS o n endothelial cells is of clinical relevance, mice were treated with t otal body irradiation (TBI) and inoculated with a single dose of LPS, Immunohistochemical analyses of murine tissues demonstrated that LPS s uperinduces IR-triggered ICAM-1 also in vivo. These findings may be of clinical importance as they suggest that the endothelium is activated after radiotherapy or TBI used for conditioning in bone marrow transp lantation, The activated endothelium in turn may facilitate the accumu lation of effector cells at sites of inflammation.