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Glucocorticoids

Anthony J. Frew

Genomic Actions of Glucocorticoids
Glucocorticoids (GCs) are among the most commonly prescribed
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drugs and are used for a wide range of medical conditions. More The antiinflammatory and immunomodulatory effects of GCs are
than 60 years after their introduction into clinical practice, they mainly mediated by genomic mechanisms (Figs. 86.1 and 86.2).
remain the most important and most frequently employed class Their lipophilic structure and low molecular mass allow GCs
of antiinflammatory drugs, and their use continues to increase, to pass easily through the cell membrane and bind to cytosolic
with about 10 million new prescriptions issued for oral GCs each glucocorticoid receptors (cGCRs). Ultimately this either induces
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year in the United States. Community survey data suggest that the synthesis of regulatory proteins (“transactivation”) or inhibits
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0.5% of the general population and 1.75% of women aged over their synthesis (“transrepression”). About 10–100 genes per
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55 years are taking oral GCs. About 56–68% of patients with cell are directly regulated by GCs, but many other genes are
rheumatoid arthritis (RA) are treated more or less continuously regulated indirectly through interaction with transcription factors
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with GCs. Although GCs are relatively inexpensive, total market and coactivators (see below). It has been estimated that GCs
volume is valued at ≈US$10 billion per year. 2 influence the transcription of approximately 1% of the entire
GCs are widely used because they are the most effective (and genome.
cost-effective) antiinflammatory and immunomodulatory drugs
available. However, GCs can cause serious adverse effects, Structure of the Cytosolic Glucocorticoid Receptor
especially when used incorrectly. The nonactivated cGCR (cGCRα) is a 94-kilodalton (kDa) protein
held in the cytoplasm as a multiprotein complex, consisting of
MECHANISMS OF ACTION several heat shock proteins (hsps), including hsp90, hsp70, hsp56,
and hsp40 (chaperones) (Fig. 86.3). The cGCR interacts with
The way that GCs are used in different clinical conditions is immunophilins, p23, and several kinases of the mitogen-activated
essentially empirical, as there is only limited evidence to support protein kinase (MAPK) signaling system, including Src, which
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current practice in specific clinical settings. In general, GC dosages also act as molecular (co)chaperones (see Figs. 86.1 and 86.3).
are increased in parallel with the clinical activity and severity of The general function of molecular (co)chaperones is to bind
the disease under treatment. The rationale for this approach is and stabilize proteins at intermediate stages of folding, assembly,
that higher dosages increase GC receptor saturation in a dose- translocation, and degradation. With regard to cGCR, they also
dependent manner (Table 86.1), which intensifies the therapeuti- regulate cellular signaling, which includes (i) stabilizing a high-
cally relevant, genomic actions of GCs. Moreover, with increasing affinity conformational state of cGCR; (ii) opening the GC-
dosages, additional and qualitatively different, nonspecific, binding cleft to be accessed by GCs; and (iii) stabilizing the
nongenomic actions of GCs come into play (see Table 86.1). binding of the GCR to the promoter. 1
The first step in assembling the multiprotein cytosolic complex
is adenosine triphosphate (ATP)–dependent and hsp40(YDJ-1)–
KEY CONCEPTS dependent formation of a cGCR–hsp70 complex that primes
Characteristics Applying to Genomic Actions the receptor for subsequent ATP-dependent activation by hsp90,
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Hop, and p23. The GCR consists of different domains with
• Physiologically relevant distinct functions: an N-terminal domain; a DNA-binding domain
• Therapeutically effective at all dosages, even very small ones (low
dose therapy). (DBD); and a ligand-binding domain (LBD) (see Fig. 86.3). The
• Slow; significant changes in the regulator protein concentrations are N-terminal domain serves transactivation functions, especially
not seen within less than 30 minutes because of the time required within the “τ1” region. A zinc finger motif, a sequence common
for cytosolic glucocorticoid receptor (cGCR) activation/translocation, to many DNA-interacting proteins, is found twice within the
transcription, and translation effects. DBD. The LBD consists of 12 α helices, several of which help
• The glucocorticoid (GC)–induced synthesis of regulator proteins can form a hydrophobic ligand-binding pocket. The cGCR contains
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be prevented by inhibitors of transcription (e.g., actinomycin D) or another major transactivation region (“τ2”) that can interact
translation (e.g., cycloheximide).
with the above-mentioned cofactors (see Fig. 86.3). Following
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