Biology Reference
In-Depth Information
3.2.2 How Glucocorticoids Work
To understand how PDE4 inhibitors and glucocorticoids might interact to deliver
superior clinical benefit, an appreciation of the mechanisms of action of glucocor-
ticoids is required. In asthmatic subjects, in vivo, glucocorticoids produce a pro-
found reduction in pulmonary leukocyte burden that is associated with chronic
inflammation (Barnes
2006
). In particular, glucocorticoids dramatically reduce
eosinophil numbers in the lung by inhibiting the expression of numerous proin-
flammatory mediators, including cytokines, chemokines, inflammatory proteins,
and their receptors, as well as adhesion molecules. The primary mechanism of
this anti-inflammatory action of glucocorticoids is the repression of proinflamma-
tory gene expression (Newton
2000
).
Mechanistically, glucocorticoids act via the GR (NR3C1), which on binding
glucocorticoid translocates from the cytoplasm to the nucleus, where it interacts
with DNA sequences in the promoters of target genes to modulate their transcrip-
tional activity (Pratt et al.
2004
). These regulatory sites were initially described as
palindromic sequences referred to as simple glucocorticoid response elements
(GREs), to which the agonist-bound GR interacted as a dimer (Dahlman-Wright
et al.
1991
). However, it is now clear that the GR can interact with multiple
transcription factors to promote transcription via a multitude of discrete interactions
(Newton and Holden
2007
). Collectively, this ability to induce gene transcription is
known as
trans
activation and this was previously perceived as being responsible for
many of the adverse effects, often metabolic, that manifest following longer term,
high-dose glucocorticoid therapies (Schacke et al.
2002
). However, ongoing char-
acterization of the human genome has led to the realization that many hundreds of
genes are induced by glucocorticoids and many of these have, potentially, profound
anti-inflammatory activity (see Newton and Holden
2007
). Furthermore, many
investigators report that the ability of glucocorticoids to repress proinflammatory
gene expression is abrogated under conditions of translational or transcriptional
blockade, thereby implying that these repressive effects are themselves dependent
on gene expression (Newton and Holden
2007
). Thus, genes such as glucocorticoid-
induced leucine zipper (
GILZ
), mitogen-activated protein kinase phosphatase
(
MKP
) 1, and tristetraprolin are all induced by glucocorticoids and may, variously,
repress proinflammatory gene expression at transcriptional, posttranscriptional,
translational, or even posttranslational levels (Newton and Holden
2007
). Alterna-
tively, the agonist-bound GR is believed to directly interfere with the induction of
key proinflammatory transcription factors such as nuclear factor kappaB (NF-
k
B)
and activator protein (AP)-1 (De Bosscher et al.
2003
). In this model, the GR is
believed to recruit repressor molecules, such as histone deacetylase (HDAC) 2, to
reduce transcriptional activation (Ito et al.
2000
). However, the distinction between
direct repression by the GR (often referred to as
trans
repression) and the repression
of transcription that is exerted by glucocorticoid-induced genes has become eroded
with the findings that glucocorticoid-inducible genes including
GILZ
and
MKP-1
may both play roles in the repression of NF-
k
B- and AP-1-dependent transcription
(Diefenbacher et al.
2008
; Eddleston et al.
2007
; King et al.
2009
; Mittelstadt and
