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 of conditioning related release of proinflammatory cytokines in induction of acute graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation (BMT). In the present report we show that ionizing radiation (IR) in a clinical relevant dose upregulates intercellular adhesion molecule 1 (ICAM-1) on cultured human microvascular endothelial cells (HMEC). Bacterial endotoxin (lipopolysaccharide, LPS) in a concentration corresponding to serum levels seen during clinical endotoxemia, is capable of further enhancing ICAM-1 expression on irradiated cells. Adhesion assays with freshly isolated peripheral blood mononuclear cells (PBMC) revealed that increased ICAM-1 on IR-treated endothelial cells led to an increased adhesion of PBMC. Again, this effect could be superinduced by LPS. Recombinant human interleukin 10 (IL-10), an antagonistic cytokine known to function as an LPS antagonist, was able to counteract the LPS-mediated enhancement of IR-triggered ICAM-1 induction and PBMC adhesion. In contrast, IL-10 could not inhibit irradiation caused effects. IL-10 seemed to interfere with the translocation of preformed intracellular ICAM-1 to the cell membrane. To investigate whether this superinductive function of IR and LPS on endothelial cells is of clinical relevance, mice were treated with total body irradiation (TBI) and inoculated with a single dose of LPS. Immunohistochemical analyses of murine tissues demonstrated that LPS superinduces 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 transplantation. The activated endothelium in turn may facilitate the accumulation of effector cells at sites of inflammation.
Eissner
G
G
GSF Institut für Klinische Molekularbiologie, Strahlenbiologie, Molekulare Virologie, und Klinische Hämatologie, München, Germany.
Lindner
H
H
Behrends
U
U
Kölch
W
W
Hieke
A
A
Klauke
I
I
Bornkamm
G W
GW
Holler
E
E
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000528:radiation effects; D004731:Endotoxins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014916:Whole-Body Irradiation
D004731:Endotoxins; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10