Glucocorticoids
biological effects are mediated by specific intracellular
receptors (Glucocorticoid Receptors, GRs), which, in the lungs,
are mainly localised in the airway epithelial and endothelial cells, where they
are assumed to mediate the anti-inflammatory actions of ICSs.
Under resting conditions, inactive GRs are located
in the cytosol, associated with multiple chaperone proteins (which are proteins required
for the proper folding or assembly of another protein or protein complex
without being a component of the final structure).
After having penetrated the cell membrane, glucocorticoid
molecules bind to GRs, inducing their dissociation from chaperones and
the consequent formation of active GR-glucocorticoid complexes, which may act
in three different ways (Fig. 2).3
Figure 2: General mechanism of action of glucocorticoids (Adapted from NEJM 2005; 353:
1711-1723).3
- DIRECT GENOMIC PATHWAY: The GR-glucocorticoid complex moves to the
cell nucleus where it binds as a homodimer (a complex
of two identical protein
chains held together by non-covalent/weak bonds)
to specific DNA sequences called glucocorticoid-responsive
elements
(GREs). The resulting
complex recruits either co-activator or co-repressor
proteins that consequently
facilitate or inhibit gene transcription by RNA
polimerase II. This process is called trans-activation
and determines
direct genomic effects.
- INDIRECT GENOMIC PATHWAY: Alternatively,
the active GR-glucocorticoid complex may also act
as a monomer and directly
interact with other transcription
factors, such as nuclear factor (NF)-kB, which
is mainly involved
in the DNA acetylation and unwinding process due
to proinflammatory
cytokines: inhibiting this transcription factors
activity the related proinflammatory
process is blocked. This process is termed trans-repression and induces indirect genomic effects.
- NON-GENOMIC PATHWAY: Furthermore,
glucocorticoid signalling can also be mediated
by membrane associated receptors
and second messengers
(indicated as non-genomic pathway), which lead
to the induction of anti-inflammatory
proteins as well.
Glucocorticoids reduce inflammation through all
these three mechanisms.
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