The dynamics of gene expression in human lung microvascular endothelial cells after stimulation with inflammatory cytokines.
Vascular endothelium plays an essential role in the pathogenesis of vasoocclusion. The changes in the endothelial cell function can be triggered by changes in gene expression caused by interaction with cytokines and blood cells. Using cDNA arrays, we have recently reported complex patterns of gene expression after stimulation of endothelial cells with TNFalpha and IL-1beta. Better understanding of the time course of gene expression changes, their concentration dependence and reversibility after withdrawal of the offending cytokine is essential for successful prevention and therapy of vasoocclusion. Here we present a detailed study of the concentration dependence and time course of gene expression in endothelial cells after their exposure to TNFalpha and IL-1beta. We focus on the adhesion molecules (VCAM-1, ICAM-1, E-selectin) and cytokines (IL-6, GCP-2, MCP-1) that are likely to contribute to vasoocclusion. We report differences in the time course and intensity of their expression and in their response to TNFalpha and IL-1beta stimulation. We demonstrate that expression of the studied genes is upregulated by low TNFalpha concentrations that better reflect the TNFalpha levels detected in the plasma of patients developing vasoocclusion. These results help to understand the changes in the endothelium and to design rational prevention and therapy of vasoocclusion.
Zachlederová
M
M
Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
Jarolím
P
P
D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054427:Chemokine CXCL6; D019743:Chemokines, CXC / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000098:blood supply*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C111835:CCL2 protein, human; C515503:CXCL6 protein, human; D018932:Chemokine CCL2; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; D019040:E-Selectin; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1