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)

• Published in: Cytokine (Philadelphia, Pa.) Vol. 12; no. 7; pp. 992 - 1000
• Main Authors: Berger, Adam C, Alexander, H.Richard, Wu, Peter C, Tang, Guangqing, Gnant, Michael F.X, Mixon, Arnold, Turner, Ewa S, Libutti, Steven K
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2000
• Subjects: Animals; Antigens, CD - biosynthesis; Antigens, CD - genetics; apoptosis/cytokine receptors/EMAP-II/endothelial cells/tumour necrosis factor; Cytokines; Endothelium, Vascular - cytology; Enzyme-Linked Immunosorbent Assay - methods; Female; Flow Cytometry - methods; Fluorescence; Humans; Intracellular Fluid; Mice; Mice, Inbred C3H; Mice, Nude; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Receptors, Tumor Necrosis Factor - biosynthesis; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Tumor Cells, Cultured; Up-Regulation; apoptosis/cytokine receptors/EMAP-II/endothelial cells/tumour necrosis factor
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1006/cyto.2000.0687

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 2h; 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.