Tumor necrosis factor increases transcription of the heparin-binding epidermal growth factor-like growth factor gene in vascular endothelial cells.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a recently identified, potent vascular smooth muscle cell (SMC) mitogen of macrophage origin. To determine whether this gene is transcribed and regulated in vascular endothelial cells, we measured HB-EGF mRNA levels in human umbilical vein endothelial cells (HUVEC) by RNA blot analysis with an HB-EGF cDNA probe. The base-line level of HB-EFG mRNA in HUVEC in culture was low. However, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta markedly increased HB-EGF mRNA levels in HUVEC by 12- and 7-fold, respectively, and induction of the gene by TNF-alpha was both dose- and time-dependent. In response to TNF-alpha, HB-EGF mRNA levels quickly increased and peaked at 1 h, indicating that HB-EGF belongs to the family of immediate early genes. In nuclear run-off experiments, TNF-alpha increased the rate of HB-EGF gene transcription by 3.2-fold. To our knowledge this is the first demonstration that the HB-EGF gene is transcribed in vascular endothelial cells. The inducible transcription of this potent SMC mitogen gene in endothelial cells suggests that HB-EGF may have an important role in the pathogenesis of atherosclerosis.
Yoshizumi
M
M
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Kourembanas
S
S
Temizer
D H
DH
Cambria
R P
RP
Quertermous
T
T
Lee
M E
ME
D001483:Base Sequence; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000235:genetics*; D015723:Gene Library; D006493:Heparin / Q000235:genetics*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007700:Kinetics; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics / Q000302:isolation & purification; D011994:Recombinant Proteins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins
C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D007371:Interferon-gamma; D006493:Heparin; D004247:DNA; D013755:Tetradecanoylphorbol Acetate