Biomedical Engineering Reference
In-Depth Information
VCAM-1) expressed from both leukocytes and vascular endothelium (Carlos and
Harlan 1994, Haverslag
et al.
2008). During recent years, ef orts have intensii ed to
elucidate the links between activation of PI3K/Akt-NF-κB signaling transduction
pathways and the regulation of gene expression of adhesion molecules. However, up
to now, very few comprehensive studies have investigated the molecular signaling
interaction between the PI3K and NF-κB pathways in inl ammatory cytokine-
elicited upregulation of VCAM-1 at the levels of gene promoter, PI3K activity,
and NF-κB modulation, simultaneously. Further understanding of the crosstalk
and interaction between vascular endothelial cells and inl ammatory leukocytes
will lead us to new avenues for the prevention and therapy of inl ammatory and
cardiovascular diseases as well as cancer. One of the crucial proteins is VCAM-1,
a member of the Ig superfamily that mediates leukocyte binding to the endothelial
cell through its interaction with the leukocyte's integrin counterreceptor very late
activation antigen 4 (VLA-4). Because of the selective expression of VLA-4 on
monocytes and lymphocytes, but not neutrophils, VCAM-1 plays an important role
in mediating mononuclear leukocyte-selective adhesion. However, the molecular
mechanisms of VCAM-1 upregulation in the inl ammatory pulmonary system are
still not completely understood. We investigated the ef ects of an inl ammatory
cytokine, HIMF, in the regulation of VCAM-1 expression and the results showed
that VCAM-1 gene expression is closely controlled by HIMF-induced PI3K/Akt-
NF-κB activation (Tong
et al.
2006). Blocking PI3K/Akt activity or inhibiting NF-
κB activation with, respectively, mutant dominant negative proteins or chemical
inhibitors signii cantly prevented VCAM-1 gene upregulation. h ese i ndings
certainly provided a typical example for inl ammatory cytokine-induced adhesion
molecule overproduction and further facilitate our understanding of the process
of leukocyte-endothelium interaction and inl ammatory cell migration.
BACKGROUND
The PI3K/Akt Signaling Transduction Pathway
PI3Ks are grouped into three classes (I-III) with dif erent isoforms in class I as IA
(including PI3Kα, β and δ) and IB (PI3Kγ), according to their substrate preference
and sequence homology (Engelman
et al.
2006). h e coexistence of classes of PI3K
and their isoforms in either the same or dif erent type of cells has distinct functions
in cellular signal transduction and is accountable for the diversii ed biological
roles in those cells. Class IA PI3Ks, heterodimers that consist of a p85 regulatory
subunit and a p110 catalytic subunit, are mainly involved in regulating cellular
proliferation and survival in response to activation of protein tyrosine kinase-
coupled growth factor receptors. Whereas class IB PI3K (PI3Kγ), a heterodimer
that consists of a p101 regulatory subunit and a p110γ catalytic subunit, allows
fast-acting, heterotrimeric G protein-coupled receptors to access PI3K signaling
