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1166 ParT TEN Prevention and Therapy of Immunological Diseases

TABLE 86.1 Current Knowledge on the relationship Between Clinical Glucocorticoid (GC)
Dosing and Cellular GC actions
Terminology Cytosolic Glucocorticoid
(Mg Prednisone Genomic actions Unspecific receptor (cGCr)–Mediated
Equivalent Per Day) Clinical application (receptor Saturation) Nongenomic actions Nongenomic actions
Low dose (≤7.5) Maintenance therapy for many + (<50%) − ?
rheumatic diseases
Medium dose Initially given in primary ++ (>50% – <100%) (+) (+)
(>7.5 – ≤30) chronic rheumatic diseases
High dose (>30 – ≤100) Initially given in subacute ++(+) (almost 100%) + +
rheumatic diseases
Very high dose Initially given in acute and/or +++ ([almost] 100%) ++ +(+?)
(>100 mg) potentially life-threatening
exacerbations of rheumatic
diseases
Pulse therapy (≥250 mg Particularly severe and/or +++ (100%) +++ +(++?)
for 1 or a few days) potentially life-threatening
forms of rheumatic diseases
From Buttgereit F, Straub RH, Wehling M, Burmester GR. Glucocorticoids in the treatment of rheumatic diseases. An update on mechanisms of action. Arthritis Rheum 2004;50:
3408–17, with permission.)

Genomic mechanisms Glucocorticoid Nongenomic mechanisms

mGCR
Plasma membrane
Cytosol

HSP HSP 3 4
cGCR
mGCR-mediated nonspecific
Src nongenomic m. nongenomic m.
Src 2
HSP
cGCR-mediated
nongenomic m.
Nucleus
HSP
1
cGCR-mediated Antiinflammatory, immunomodulatory
genomic m. and other (including unwanted
cGCR adverse) effects
FIG 86.1 Mechanisms of the Cellular Action of Glucocorticoids (GCs). As lipophilic substances,
GCs pass very easily through the cell membrane into the cell, where they bind to ubiquitously
expressed cytosolic glucocorticoid receptors (cGCRs). This is followed by either the classic
cGCR-mediated genomic effects (1) or by cGCR-mediated nongenomic effects (2). Moreover,
the GC is very likely to interact with cell membranes, either specifically via membrane-bound
glucocorticoid receptors (mGCRs) (3) or via nonspecific interactions with cell membranes (4).
(From Buttgereit F, Straub RH, Wehling M, Burmester GR. Glucocorticoids in the treatment of
rheumatic diseases. An update on mechanisms of action. Arthritis Rheum 2004;50:3408–17.)

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GC/cGCR binding, the hsp90 molecules and other molecular of FKBP52 and dynein to the GCR. Depending on the target
chaperones are rapidly shed. This allows translocation into the gene, transcription is then either activated (transactivation via
cell nucleus, where the GC/cGCR complex binds as a homodimer positive GRE) or inhibited (transrepression via negative GRE).
to consensus palindromic DNA sites (glucocorticoid-responsive
elements [GREs]). 5 Interactions With Transcription Factors
As well as the interactions of GC/cGCR complexes with GRE,
Translocation Into the Nucleus a further important genomic mechanism of GC action is the
Nuclear translocation of the GC/cGCR complex occurs within interaction of activated cGCR monomers with transcription
20 minutes. This may be caused by hormone-directed recruitment factors. Accordingly, although the GC/cGCR complex does