Endothelial cell anergy is mediated by bFGF through the sustained activation of p38-MAPK and NF-kappaB inhibition.
Tumors escape from immune surveillance by, among other mechanisms, the down- regulation of endothelial adhesion molecules, such as ICAM-1, and by unresponsiveness to inflammatory signals, a process mediated by angiogenic factors that is called endothelial cell anergy. Here we present the cell biological regulation of these processes. The angiogenic basic fibroblast growth factor (bFGF/FGF-2) was found to inhibit tumor necrosis factor-alpha (TNF-alpha)- induced elevation of ICAM-1, at transcriptional level. Furthermore, we found that bFGF inhibits the TNF-mediated activation of NF-kappaB by blocking phosphorylation and degradation of IkappaBalpha. We also found that bFGF induces hyperphosphorylation of p38 MAPK on endothelial cells, whereas inhibition of such kinase abrogates the effect of bFGF on the TNF-mediated activation of NF-kappaB. Thus, we suggest that bFGF acts as an inhibitor of leukocyte adhesion in tumor vessels by decreasing the ICAM-1 expression through the sustained activation of p38-MAPK and via inhibition of NF-kappaB.
Flati
V
V
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. flativ@univaq.it
Pastore
L I
LI
Griffioen
A W
AW
Satijn
S
S
Toniato
E
E
D'Alimonte
I
I
Laglia
E
E
Marchetti
P
P
Gulino
A
A
Martinotti
S
S
D002460:Cell Line; D017635:Clonal Anergy / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases