Biomedical Engineering Reference
In-Depth Information
[GR response elements (GREs), GGTACAnnnTGTTCT] and interaction
with coactivator complexes (such as steroid receptor coactivator 1
(SRC-1), p160 coactivator, and CBP via the AF-2 domain of GR (24,25).
The coactivators have HAT activity and play an intriguing role in gene tran-
scription that involves modulation of chromatin structure. Glucocorticoid
receptors binding to this partial palindromic promotor sequence-GRE
induce the transcriptional induction of anti-inflammatory genes such as
secretary leukocyte protease inhibitor (SLPI), lipocortin, mitogen-activated
protein kinase phosphatase-1 (MKP-1), IL-1 type II receptor, NF-
k
B inhi-
bitor I-kB
a
, AP-1 inhibitor-glucocorticoid-induced leucine zipper (GILZ),
and
b
-adrenergic receptor (2,24,26). Recent studies have demonstrated that
corticosteroids may also play a role in repressing the action of MAPKs such
as the extracellular regulated kinase (ERK) and JNK (27-29). Corticoster-
oids inhibit the phosphorylation and activation of JNK, resulting in a fail-
ure to phosphorylate c-Jun and Elk-1, reduced c-fos transcription and a
marked reduction in AP-1 activity (28). More recently, it has been shown
that dexamethasone can rapidly induce the dual specificity MAPK inhibitor
MKP-1 and thereby attenuate p38 MAPK activation (30-33). Rogatsky and
colleagues (34) have in turn shown reciprocal inhibition of rat GR reporter
gene activity by JNKs by a direct phosphorylation of serine 246, whereas
ERK can inhibit GR action by an indirect effect possibly through phosphor-
ylation of a cofactor. This GR-GRE binding also induced tyrosine amino-
transferase (TAT) and phosphoenolpyruvate carbocykinase (PEPCK),
which are involved in corticosteroid-induced side effects (35,36).
As well as transactivation by GR, the homodimer of activated GR
may also bind to a negative GRE (nGRE) in a manner similar to that
described for positive gene regulation, and induces transrepressive effect
on genes, such as IL-6 and prolactin (24).
In chronic inflammation, there is a coordinated expression of multiple
inflammatory genes, including cytokines, chemokines, MMP, adhesion
molecules, and inflammatory enzymes that have been activated by proin-
flammatory transcription factors, such as NF-
k
B and AP-1. This increase
in gene expression is also brought about by acetylation of core histones
around which DNA is wound and these transcription factors bind. Corticos-
teroid-bound GR directly interacts with transcriptional factors, such as NF-
k
B and AP-1, impairing their ability to induce gene expression by decreasing
the availability of NF-
k
B or AP-1 to interact with DNA (25). As the dimer-
aization defective mutant (GRdim) is capable of inhibiting NF-
k
B function,
monomer of activated GR can bind to transcriptional factors (37). More
importantly, corticosteroids at lower dose reverse the hyperacetylation of
histone at promoter of inflammatory gene by reversing histone acetylation
through the recruitment of histone deacetylase-2 (HDAC2) to the activated
coactivator complex (38). This then results in rewinding and compacting of
DNA, the exclusion of basal transcription complex (BTC) including RNA
