Tumour necrosis factor receptor I (p55) is upregulated on endothelial cells by exposure to the tumour-derived cytokine endothelial monocyte- activating polypeptide II (EMAP-II).
Endothelial monocyte activating polypeptide-II (EMAP-II) is an inflammatory cytokine known to have a role in neutrophil and macrophage chemotaxis and in apoptosis. It is a tumour-derived cytokine that sensitizes tumour vasculature to the effects of systemic TNF. In order to gain insight into the mechanism by which EMAP-II sensitizes vessels to TNF, we focused on its effects on TNF receptor expression. In human umbilical vein endothelial cells (HUVEC), TNF-R1 mRNA is increased four-fold following incubation with recombinant EMAP-II. Conditioned media from cell lines known to produce high levels of EMAP-II upregulated TNF-R1 but not TNF-R2 by up to twenty-fold compared to media controls and low expressing cell lines; this effect was blocked by anti-EMAP-II antibody. Recombinant EMAP-II upregulated TNF-R1 expression by approximately six-fold. Analysis of HUVEC lysates by ELISA showed increased expression of TNF-R1 within 2 h; TNF-R2 expression was unaffected by recombinant EMAP-II. Finally, immunohistochemistry of human melanomas in vivo showed that TNF-R1 staining is increased on the vessels of tumours known to express high levels of EMAP-II compared to low EMAP-II expressing tumours. These results suggest that EMAP-II upregulates TNF-R1 expression by endothelial cells both in vitro and in vivo. This induction of TNF-R1 expression may be the mechanism by which EMAP-II sensitizes tumour endothelium to the effects of TNF leading to haemorrhagic necrosis.
Berger
A C
AC
Surgery Branch, National Institutes of Health, Bethesda, MD 20892, USA.
Alexander
H R
HR
Wu
P C
PC
Tang
G
G
Gnant
M F
MF
Mixon
A
A
Turner
E S
ES
Libutti
S K
SK
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics*; D016207:Cytokines; D004730:Endothelium, Vascular / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005453:Fluorescence; D006801:Humans; D007424:Intracellular Fluid; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D015703:Antigens, CD; D016207:Cytokines; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; C077219:small inducible cytokine subfamily E, member 1