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CHaPTEr 86 Glucocorticoids 1167

Ligand-binding domain

Transcription
cGCR p23
A GRE COOH

Transcription τ hinge HSP90
cGCR NH 2 2 τ 2 HSP90 HSP70
B nGRE C C C C HSP56
Zn Zn SRC
C C C C and other
chaperones
cGCR
P65 P50 N-terminal DNA-binding
Transcription
No binding domain
C κB site FIG 86.3 Structure of the Cytosolic Glucocorticoid Receptor
(cGCR). The nonactivated (unligated) cGCR is a 94-kilodalton
Co-activator cGCR (kDa) protein retained in the cytoplasm as a multiprotein complex
consisting of several heat shock proteins (hsps), including hsp90,
Co-activator hsp70, hsp56, and hsp40 (chaperones). Furthermore, the cGCR
interacts with immunophilins, p23, and several kinases of the
AP-1 mitogen-activated protein kinase (MAPK) signaling system,
No binding Transcription including Src, which also act as molecular (co)chaperones. An
D AP1 site important function of molecular (co)chaperones is to stabilize a
FIG 86.2 Genomic Mechanisms of Glucocorticoids (GCs). specific conformational state of the GC which binds ligand with
This figure illustrates the different mechanisms by which the high affinity (see text). The receptor protein itself consists of
activated glucocorticoid receptor (GCR) complex leads to the different domains: an N-terminal, a DNA-binding domain (DBD),
induction or to the inhibition of transcription and finally translation/ and a ligand-binding domain (LBD). The N-terminal harbors
synthesis of specific regulator proteins. Details are given in the transactivation functions, especially within the so-called τ1 region.
text. (From Buttgereit F, Straub RH, Wehling M, Burmester GR. Another major transactivation region is τ2, which can interact
Glucocorticoids in the treatment of rheumatic diseases. An update with the above-mentioned cofactors. (From Buttgereit F, Straub
on mechanisms of action. Arthritis Rheum 2004;50:3408–17.) RH, Wehling M, Burmester GR. Glucocorticoids in the treatment
of rheumatic diseases. An update on mechanisms of action.
Arthritis Rheum 2004;50:3408–17.)

not inhibit their synthesis, it modulates the activity of AP-1 is thought to function as a negative inhibitor of cGCRα, and it
(activator protein-1), nuclear factor (NF)-κB (nuclear factor- may play a role in the clinical phenomenon of GC resistance.
κB) and NFAT (nuclear factor for activated T cells). This leads cGCRβ lacks the GC-binding domain that is needed for activation,
to inhibition of nuclear translocation and/or function of these and as it does not undergo ligand-dependent downregulation,
transcription factors and, thus, to inhibition of expression of it has a longer half-life than the active form (cGCRα). It is thought
many immunoregulatory and inflammatory cytokines. Possible that the likely mechanism of the dominant negative activity of
5
mechanisms include : cGCRβ is through the formation of inactive heterodimers with
• Synthesis of IκB (a specific inhibitor of NF-κB) induced cGCRα. 10
through GC/cGCR complex–GRE interaction (see Fig. 86.2A)
• Protein–protein interaction of the GC/cGCR complex with Posttranscriptional and Posttranslational Mechanisms
transcription factors through binding to their subunits (see GCs also act through posttranscriptional and posttranslational
Fig. 86.2C), which prevents their DNA binding mechanisms, including reduction of the half-life of cytokine
• Competition for nuclear coactivators between the GC/cGCR messenger RNA (mRNA) and downregulation of the GCR,
complex and transcription factors (see Fig. 86.2D) via reduced mRNA levels and reduced stability of the GCR
Inhibition of transcription factor function and the resultant protein.
inhibition of protein expression are referred to as transrepression.
Numerous genes are regulated by this mechanism. Many adverse
effects of GCs are caused by transactivation (induced synthesis
of regulator proteins), whereas most antiinflammatory effects KEY CONCEPTS
are mediated by transrepression (inhibited synthesis of regula- Glucocorticoid (GC) Effects on Immune Cells
tor proteins). This differential molecular regulation underlies
current drug-discovery programs aimed at developing dissociated • Inhibit leukocyte traffic and access of leukocytes to the site of
cGCR-ligands. 2 inflammation
• Interfere with functions of leukocytes, fibroblasts, and endothelial
The cGCRβ Isoform cells
• Suppress the production and actions of humoral factors involved in
The cGCRβ isoform is an alternative splicing variant of cGCRα the inflammatory process
that does not bind GCs or activate gene expression. This isoform