Flati V, Pastore L I, Griffioen A W, Satijn S, Toniato E, D'Alimonte I, Laglia E, Marchetti P, Gulino A, Martinotti S
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Int J Immunopathol Pharmacol. 2006 Oct-Dec;19(4):761-73. doi: 10.1177/039463200601900406.
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.
肿瘤通过多种机制逃避免疫监视，其中包括下调内皮细胞黏附分子（如细胞间黏附分子-1，ICAM-1），以及对炎症信号无反应，这一过程由血管生成因子介导，称为内皮细胞无反应性。在此我们阐述这些过程的细胞生物学调控。血管生成性碱性成纤维细胞生长因子（bFGF/FGF-2）被发现在转录水平抑制肿瘤坏死因子-α（TNF-α）诱导的ICAM-1升高。此外，我们发现bFGF通过阻断IκBα的磷酸化和降解来抑制TNF介导的核因子κB（NF-κB）激活。我们还发现bFGF诱导内皮细胞上p38丝裂原活化蛋白激酶（p38 MAPK）的过度磷酸化，而抑制这种激酶可消除bFGF对TNF介导的NF-κB激活的影响。因此，我们认为bFGF通过持续激活p38-MAPK并抑制NF-κB来降低ICAM-1表达，从而作为肿瘤血管中白细胞黏附的抑制剂。
