ABSTRACT
Infl ammatory cytokines dramatically and selectively modulate the transcription and translation of adhesion molecules and chemoattractant proteins in leukocytes and endothelial cells. Cytokines commonly found in infl ammatory lesions, such as TNF-α and interleukin-1 (IL-1), induce the concurrent expression of VCAM-1, ICAM-1, and E-selectin in endothelial cells to increase its adhesiveness (Haraldsen et al. 1996, Sawa et al. 2007). IL-4 synergistically with other cytokines increases adhesion of lymphocytes and induces VCAM-1. It is likely that the precise mixture of chemoattractants and cytokine produced at infl ammatory sites in vivo determines which types of leukocytes emigrate. Th e elevated and prolonged expression of VCAM-1, ICAM-1 and E-selectin has been observed in both experimental models and human infl ammatory processes. Treatment of endothelial cells with bacterial lipopolysaccharide (LPS) in vitro as well as in vivo upregulates VCAM-1, ICAM-1, and E-selectin expression in endothelial cells (Van Kampen and Mallard 2001a, b, Sawa et al. 2007). However, the expression kinetics for these proteins varies with the stimulants. TNF-α and LPS induced similar VCAM-1 expression at 1 hr, followed by a signifi cant increase at 3 hr that was maintained until 48 hr. Meanwhile, the expression of ICAM-1 mRNA peaked at 12-18 hr and then diminished but remained at above baseline level up to 72 hr. LPS-stimulated E-selectin mRNA expression peaked at 6 hr, followed by a decline to baseline by 24 hr. Conversely, TNF-α stimulated signifi cant upregulation of E-selectin mRNA by 6 hr, followed by a gradual increase and eventually sharp increase between 18 and 72 hr. Furthermore, to investigate the role of the signaling transduction pathways participating in the regulation of adhesion molecule gene upregulation, the activation of the PI3K/Akt-NF-κB signaling pathways has been brought to the central arena. Studies have demonstrated that integrin upregulation is mediated by increased PI3K/Akt activities in cytohesin-1-induced β2-integrin production in Jurkat cells (Nagel et al. 1998). In platelets the activation of integrin is largely controlled by PI3K (Roberts et al. 2004, Schoenwaelder et al. 2007). As most of the adhesion molecule genes possess NF-κB binding site in their promoter region, suppression of NF-κB activation with its inhibitor MG-132, signifi cantly attenuated TNF-α and IL-1β induced chemokine (including MGSA, RANTES, MCO-1, M-CSF) and ICAM-1 upregulation in human retinal pigment epithelial cells. Moreover, TNF-α and IL-1β also caused degradation of IκB, NFκB nuclear translocation, and increased NF-κB DNA binding activity. Similar results of NF-κB activation were found in adenovirus-induced ICAM-1 induction in A549 cells (Voraberger et al. 1991). However, most of the studies mentioned above are limited either in the cellular or transcriptional and translational levels, which resulted in our current incomplete understanding of the exact molecular mechanisms of PI3K/Akt-NF-κB modulated leukocyte-endothelium interaction in the aspects of adhesion molecule gene expression during the infl ammatory process.
