Biomedical Engineering Reference
In-Depth Information
VCAM-1 gene expression, which then facilitates the monocyte adherence and
emigration into the pulmonary parenchyma. h is chapter reviews the current
data on the role of the PI3K/Akt-NF-κB signaling pathways as a strong regulator
for adhesion molecule gene expression and uses the HIMF-induced inl ammatory
responses as a typical model to explore the changes and importance of the PI3K/
Akt-NF-κB in inl ammation. Of greater importance, the data reviewed in this
article strongly suggest that modulation of the PI3K/Akt-NF-κB signaling pathways
can alter the expression levels of adhesion molecule. h us, manipulation of the
endogenous PI3K/Akt-NF-κB signaling pathway may represent novel preventive
and therapeutic approaches to management of important diseases such as acute or
chronic inl ammation and cancer as well.
INTRODUCTION
Over the past decades, extensive research to explore the network and crosstalk
among the dif erent signaling transduction pathways has uncovered multiple
levels of complexity dictating that no single pathway operates in isolation and that
all pathways are small parts of fully integrated networks within the cell. h is is
certainly true of the PI3Ks-Akt pathway; and several studies have demonstrated
that PI3K-Akt signaling can activate NF-κB transcription factor downstream of
stimuli, such as TNF-α, and PDGF. PI3Ks are the prominent members of a unique
and conserved family of intracellular lipid kinases that catalyze the phosphorylation
of the 3¢-hydroxyl group of phosphatidylinositol and phosphoinoditides in the
inner leal et of the plasma membrane (Engelman
et al.
2006). h is reaction leads
to the activation of versatile intracellular signaling pathways that regulate diverse
functions including cell proliferation, dif erentiation, survival, metabolism,
and migration (Cantley 2002). h e PI3K signaling transduction pathways
play imperative roles in the maintenance of normal cell function as well as in
disease conditions including cancer and inl ammation. PI3Ks participate in the
inl ammatory processes by upregulating inl ammatory related genes such as
cytokines, chemokines, growth factors, and adhesion molecules via the activation
of Akt and transcription factors (TFs), such as AP1, NF-κB. Vice versa, many of
these inl ammatory proteins also use the PI3K/Akt-NF-κB signaling pathways as
their signaling carriers to execute their biological functions (Hacker and Karin
2006, Hawkins and Stephens 2007, Manning and Cantley 2007).
Inl ammatory cell migration and sequestration into the airway walls and the
parenchyma of the alveolar compartments are the characteristic features of acute
and chronic inl ammation in the pulmonary system. Recent studies have revealed
that this process is a dynamically sequential cascade. Cooperative and ei cient
leukocyte-endothelium interaction is the prerequisite. Leukocyte extravasation is
mediated by several cell adhesion molecules including selectins (P-, E- and L-),
integrins, and members of the immunoglobulin gene (Ig) superfamily (ICAM-1 and
