[Pathogenetic role of tissue factor in endothelial-injury in graft-versus-host disease].
OBJECTIVE
To study the pathogenetic role of tissue factor (TF) in endothelial-injury in GVHD.


METHODS
Gene and protein expressions of TF in the organs of allogenic hematopoietic stem cell transplantation (allo-HSCT) and autologous HSCT (auto-HSCT) mice were determined by real-time PCR and Western blot. The effect of allogeneic T lymphocytes on the expression of TF and other cytokines and activation of MAPKs in human umbilical vein endothelial cells (HUVECs) was detected by flow cytometry, real-time PCR or Western blot. The influence of TF antibodies (SB203580 and SP600125) on allogeneic T lymphocytes-induced cytokines expression was also tested.


RESULTS
(1) TF gene and protein expression in the liver, skin, small intestine and stomach of allo-HSCT mice was significantly elevated about 15.1+/-2.1, 5.5+/-1.4, 9.7+/-2.3, 14.2+/-2.9 folds and 13.5+/-2.7, 6.2+/-0.9, 7.9+/-1.6, 15.3+/-3.2 folds respectively compared with that of auto-HSCT mice. (2) Allogeneic CD4+ CD8+ T lymphocytes significantly enhanced TF, VCAM-1, TNF-alpha, IFN-gamma and IL-6 expression in TNF-alpha prestimulated HUVECs. (3) Allogeneic T lymphocytes enhanced p38MAPK and JNK phosphorylation in HUVECs, but did not affect ERK phosphorylation. p38 MAPK JNK inhibitors SB203580 and SP600125 reduced allogeneic T lymphocytes-induced TF expression in HUVECs. (4) SB203580 and SP600125 down-regulated allogeneic T lymphocytes-induced VCAM-1, TNF-alpha, IFN-gamma, IL-6 expression in HUVECs.


CONCLUSIONS
TF mediates vascular endothelial-injury and activation in GVHD via phosphorylation of p38MAPK and JNK.
Li
Quan
Q
Institute of Hematology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Zhang
Jian
J
Li
Wei-ming
WM
Zou
Ping
P
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000473:pathology*; D004730:Endothelium, Vascular / Q000166:cytology; D006086:Graft vs Host Disease / Q000378:metabolism / Q000473:pathology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013601:T-Lymphocytes; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000873:Anthracenes; D007093:Imidazoles; D015850:Interleukin-6; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D007371:Interferon-gamma; D013925:Thromboplastin; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580