Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells.
Tumor necrosis factor (TNF) dramatically alters the levels of various surface components of the blood vessel wall, such as blood coagulation enzyme receptors, leukocyte-adhesive receptors, and class 1 major histocompatibility complex antigens, which may have relevance to its effects in septic shock, angiogenesis, and tumor growth. However, the precise mechanism by which the cytokine is able to accomplish this remodeling of the endothelial cell surface has not been defined. We have demonstrated that exposure of bovine and human endothelial cells to TNF leads to suppression of the functional cell surface thrombin receptor, thrombomodulin (TM), and TM mRNA of virtually identical magnitude. The cytokine has no significant effect on the stability of TM mRNA or endothelial receptor turnover. Nuclear run-on studies reveal that the treatment of endothelial cells with TNF for short periods reduces TM gene transcription to as little as 3% of control values and that this inhibition does not require new protein synthesis.
Conway
E M
EM
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139.
Rosenberg
R D
RD
D000546:Amanitins / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D004730:Endothelium, Vascular / Q000378:metabolism*; D005796:Genes / Q000187:drug effects*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D018179:Receptors, Thrombin; D013489:Suppression, Genetic / Q000187:drug effects*; D013917:Thrombin / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000546:Amanitins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; D014409:Tumor Necrosis Factor-alpha; D013917:Thrombin