Biomedical Engineering Reference
In-Depth Information
Inflammatory Cytokines, Adhesion Molecule Activation, and
Gene Expression via PI3K/Akt-NF-
k
B Signaling Pathways
Inl 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 inl 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 inl ammatory
sites in vivo determines which types of leukocytes emigrate. h e elevated and
prolonged expression of VCAM-1, ICAM-1 and E-selectin has been observed
in both experimental models and human inl 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 signii 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 signii 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,
signii 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, NF-
κB 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 inl ammatory
process.
