NF‐κB, but not p38 MAP Kinase, is required for TNF‐α‐induced expression of cell adhesion molecules in endothelial cells

Abstract

In response to inflammation stimuli, tumor necrosis factor-α (TNF-α) induces expression of cell adhesion molecules (CAMs) in endothelial cells (ECs). Studies have suggested that the nuclear factor-κB (NF-κB) and the p38 MAP kinase (p38) signaling pathways play central roles in this process, but conflicting results have been reported. The objective of this study is to determine the relative contributions of the two pathways to the effect of TNF-α. Our initial data indicated that blockade of p38 activity by chemical inhibitor SB203580 (SB) at 10 μM moderately inhibited TNF-α-induced expression of three types of CAMs; ICAM-1, VCAM-1 and E-selectin, indicating that p38 may be involved in the process. However, subsequent analysis revealed that neither 1 μM SB that could completely inhibit p38 nor specific knockdown of p38α and p38β with small interference RNA (siRNA) had an apparent effect, indicating that p38 activity is not essential for TNF-α-induced CAMs. The most definitive evidence to support this conclusion was from the experiments using cells differentiated from p38α knockout embryonic stem cells. We could show that deletion of p38α gene did not affect TNF-α–induced ICAM-1 and VCAM-1 expression when compared with wild type cells. We further demonstrated that inhibition of NF-κB completely blocked TNF-α-induced expression of ICAM-1, VCAM-1 and E-selectin. Taken together, our results clearly demonstrate that NF-κB, but not p38, is critical for TNF-α-induced CAM expression. The inhibition of SB at 10 μM on TNF-α-induced ICAM-1, VCAM-1 and E-selectin is likely due to the nonspecific effect of SB.

Endothelial paxillin and focal adhesion kinase (FAK) play a critical role in neutrophil transmigration

“…Studies have shown that in some systems, FAK can affect NF-kB signaling [39]. NF-kB activation by TNF-a is critical for appropriate upregulation of cell adhesion molecules such as E-selectin and ICAM-1 [40]; thus one interpretation of the data was that we had disrupted TNF-a signaling resulting in a loss of adhesion and activation molecule expression. Without proper expression of these molecules, neutrophils will not roll, adhere and transmigrate.…”

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…This induction involves NF-kB activation in the stromal cells and requires leukemia cell/stromal cell contact, which is in part mediated by VLA-4/ VCAM-1 interaction. VLA-4/VCAM-1 interaction is reported to activate NF-kB (Zohlnhofer et al 2000), and NF-kB, in turn, up-regulates VCAM-1 (Rajan et al 2008), suggesting a positive feedback loop reinforcing VLA4 þ CML cell binding to the VCAM-1-expressing stromal cells, thereby ensuring PlGF production. Stromal cell-derived PlGF then promotes proliferation and metabolism of the CML cells.…”

E-/P-selectins and colon carcinoma metastasis: first in vivo evidence for their crucial role in a clinically relevant model of spontaneous metastasis formation in the lung

“…Blocking experiments with HPA showed that adhesion of breast cancer cells with HPApositive glycotopes to TNFa-activated endothelial cells could be blocked by HPA, whereas this was not the case with HPA-negative breast cancer cells (Valentiner et al, 2005). As TNFa stimulates the expression of the endothelial (E) and platelet (P) selectins on the luminal surface of endothelial cells (Rajan et al, 2008), it is attractive to hypothesize that HPA-positive glycoconjugates exert an effect as ligands for the two selectins. These adhesion molecules bind to glycotopes on leukocytes and are known to be key players in endothelial cell interaction and in trafficking of leukocytes and in mediating tethering, rolling and endothelial activation (Sperandio, 2006).…”