Pharmacodynamics of glucocorticoids

C. Strehl, C.M. Spies, F. Buttgereit

Department of Rheumatology and ABSTRACT and anti-allergic effects on primary and

Clinical Immunology, Exogenous glucocorticoids (GCs) are secondary immune cells, tissues and
Charité-Universitätsmedizin Berlin, used as anti-inflammatory and immu- organs via different mechanisms of
Campus Mitte, Berlin, Germany.
nosuppressive drugs in the treatment action in a dose-dependent manner (1-
Cindy Strehl, Dipl.-Biochem of a wide range of rheumatic and other 3). The overall physiological effect of
Cornelia M. Spies, MD
inflammatory diseases. GCs exert their endogenous glucocorticoid hormones
Frank Buttgereit, MD, Professor
immunosuppressive, anti-inflammatory released by the adrenal cortex is to in-
Please address correspondence to:
Dr Cornelia M. Spies,
and anti-allergic effects on primary and crease blood glucose concentrations by
Department of Rheumatology and secondary immune cells, tissues and or- opposing the action of insulin and in-
Clinical Immunology, gans via different mechanisms of action creasing glucose production and release
Charité-Universitätsmedizin Berlin, in a dose-dependent manner. However, from the liver via gluconeogenesis,
Campus Mitte, their pleiotropic effects also lead to nu- which is especially important in situa-
Charitéplatz 1, merous adverse effects such as unwant- tions of stress (4).
10117 Berlin, Germany. ed metabolic effects and osteoporosis. Hench and his colleagues had noted a
E-mail: [Link]@[Link]
The mechanisms of action include the correlation between improvement of
Received and accepted on July 27, 2011. classical genomic mechanism resulting disease activity in patients with rheu-
Clin Exp Rheumatol 2011; 29 (Suppl. 68): from activation of the cytosolic gluco- matoid arthritis (RA) and the incidence
S13-S18. corticoid receptor (cGCR), non-specif- of jaundice or pregnancy (5). They con-
© Copyright CLINICAL AND ic, non-genomic effects caused by inter- cluded that there was likely an “anti-
EXPERIMENTAL RHEUMATOLOGY 2011.
actions with cellular membranes, sec- rheumatic factor” which is “neither
ondary non-genomic effects initiated by a product of the liver nor a unisexual
Key words: pharmacodynamics,
the cGCR and specific interactions with hormone” (5-7), and this finally led to
glucocorticoid, effects, mechanisms,
a membrane-bound glucocorticoid re- the application of synthesised cortisone
glucocorticoid receptor, genomic
ceptor (mGCR). Optimised glucocorti- to treatment of RA. Initially, a female
effects, non-genomic effects,
coids, such as selective glucocorticoid patient with severe disease was treated
endogenous glucocorticoids,
receptor agonists, are being devel- with cortisone in September 1948, with
exogenous glucocorticoids,
oped to minimise the adverse effects the result of a dramatic improvement of
11β-HSD, immunostimulatory,
many patients experience, especially if the disease activity (6). Further patients
pre-receptor metabolism
GCs are given at higher dosages over were treated as well and the use of GCs
longer periods of time. Immunostimu- was disseminated over the whole field
latory effects of low concentrations of of rheumatology and medicine.
endogenous glucocorticoids and the GCs were used to treat numerous dis-
influence of pre-receptor metabolism eases, and the potential of these drugs
appear of interest for further investiga- to induce adverse effects became obvi-
tion. The most important approach to ous. Unwanted effects on metabolism,
optimise the risk-benefit ratio of GCs bone tissue, muscles, eyes and skin, and
is to understand in more detail how increased susceptibility to infections oc-
the molecular mechanisms of genomic cur after treatment with higher GC dos-
and non-genomic GC actions – and ages over longer periods of time (3, 8).
their dose-dependency – mediate the These adverse events led to synthesis of
clinically wanted benefits but also the new GC agents in the 1950-1960s, e.g.
known adverse effects. prednisolone and methylprednisolone
exerting stronger anti-inflammatory
Introduction and immunosuppressive potencies, but
Exogenous glucocorticoids (GCs) are weaker mineralocorticoid activities
the most commonly used anti-inflam- such as sodium/water retention and po-
matory and immunosuppressive drugs tassium excretion (9).
in the treatment of a wide range of In this review we summarise current
rheumatic and other inflammatory dis- knowledge of pharmacodynamics of
eases. These substances exert their im- glucocorticoids, including (1) the cel-
Competing interests: none declared. munosuppressive, anti-inflammatory lular effects of GCs on immune cells,

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Pharmacodynamics of glucocorticoids / C. Strehl et al.

(2) the therapeutic effects of GCs, (3) process is usually characterised by an increased risk of infection, depression,
dose-effect-correlations of glucocorti- up-regulated synthesis of mediators cataracts, thinning and ekchymoses of
coids with adverse effects, (4) mecha- of inflammation such as cytokines or the skin (3, 8, 18, 19).
nisms of glucocorticoid actions, (5) prostaglandins, which finally leads to The main aim of a successful GC
genomic effects mediated by the cyto- the typical signs of inflammation: pain, therapy is a sufficient treatment of the
solic glucocorticoid receptor (GCR), swelling, and loss of function (10). underlying disease while minimis-
(6) rapid, non-genomic effects of GCs GCs inhibit nuclear translocation and ing the dose of the administered GC
and (7) optimised conventional GCs the function of proinflammatory tran- in order to prevent the occurrence of
and new drugs. scription factors such as activator adverse effects. Therefore, ‘low-dose’
protein 1 (AP-1) or nuclear factor-κB glucocorticoid therapy, i.e. prednisone-
Cellular effects of glucocorticoids (NFκB), which are involved in the equivalent doses of less than 7.5 mg
on immune cells regulation of the expression of pro-in- per day, is regarded as optimal main-
Commonly used glucocorticoids like flammatory genes (12-14). The synthe- tenance therapy for many patients with
prednisone, prednisolone, methylpred- sis of proinflammatory cytokines, e.g. rheumatic diseases requiring use of
nisolone or dexamethasone mediate interleukin-1 (IL-1), IL-6 and tumour GCs (20). These oral doses result in
many anti-inflammatory and immu- necrosis factor alpha (TNF-α), is dose- a saturation of the GCR of less than
nomodulatory effects on primary and dependently reduced as one key result 40–50% and are known to result in
secondary immune cells, tissues and or- of the so-called “transrepression” (3, rather mild adverse effects (10, 17, 21).
gans (1). On the cellular level, decreas- 11). These mechanisms may explain More than 50% receptor saturation is
es are seen in the number of circulating in large part retardation of radiologi- seen with prednisone-equivalent doses
monocytes/macrophages, their synthe- cal progression in rheumatoid arthritis of 7.5–30 mg per day. The so-termed
sis of pro-inflammatory cytokines and (RA), as TNF-α and IL-1 stimulate the ‘medium doses’ may be initially given
prostaglandins and their expression of production of receptor activator of nu- in primary chronic rheumatic diseases,
MHC class II molecules and Fc recep- clear factor kappa B ligand (RANKL). but are known to have dose-depend-
tors. A reduction of circulating T-cells RANKL supports the generation of ent and considerable adverse effects if
and their production and action of IL- mature and active osteoclasts, respon- used for longer periods of time (2, 18).
2 (and other cytokines) also is seen. sible for bone resorption and erosions Therapy with prednisone-equivalent
Furthermore, GCs used therapeutically in RA (15, 16). doses of 30–100 mg per day is termed
lead to a lower number of eosinophil On the other hand, treatment with GCs ‘high-dose’ glucocorticoid therapy,
and basophil granulocytes while the results in induced synthesis of anti- with an almost complete GCR satu-
number of circulating neutrophil granu- inflammatory proteins (e.g. lipocortin ration. These doses often result in an
locytes is increased. GC treatment af- 1, inhibitor of NFκB (IκB)), and also successful initial treatment of subacute
fects endothelial cells through dimin- regulator proteins which are important rheumatic diseases, but cannot be used
ished vessel permeability, expression for metabolism. This process is termed for long-term therapy because of their
of adhesion molecules, and fibroblast “transactivation”, and is thought to be high potential for serious adverse ef-
proliferation. Furthermore, production responsible for many of the adverse fects (18). Likewise, ‘very high doses’
of fibronectin and prostaglandins are effects of GCs (3, 8). (prednisone-equivalent of >100 mg
decreased by GC (1, 10, 11). per day) of GCs and ‘pulse’ therapy
In summary, therapeutically-used glu- Correlation between GC dosage, (prednisone-equivalent of ≥250 mg per
cocorticoids (1): therapeutically desired effects and day, usually given for 1–5 days) can-
• Inhibit leukocyte traffic and access adverse effects not be administered for long-term ther-
of leucocytes to the site of inflam- The most important variable in the like- apy because of severe adverse effects.
mation, lihood of therapeutically desired and Both ‘high-dose’ and ‘very high dose’
• Interfere with functions of leuco- adverse effects of GC is the dosage, regimens (i) result in a complete GCR
cytes, fibroblasts and endothelial modified by the rate of absorption, con- saturation and (ii) produce additional
cells, and centration in target tissues, and affin- rapid non-genomic GC effects (see be-
• Suppress the production and actions ity of GCs for glucocorticoid receptors low). Therefore, these doses are given
of humoral factors involved in the (GCRs) (10, 17). GCs, given at high in case of potentially life threatening
inflammatory process (1). doses and/or over long periods of time forms of rheumatic diseases, such as
are usually clinically very effective, but systemic lupus erythematosus, myosi-
Therapeutic effects of may induce numerous different adverse tis, dermatomyositis, vasculitides, and
glucocorticoids effects (8). Undesirable endocrine and are usually not indicated for most pa-
The most important therapeutic effect metabolic effects include diabetes melli- tients with rheumatoid arthritis (20).
of GCs is the inhibition of the inflam- tus, redistribution of body fat, increased
matory processes, resulting in part body weight, osteoporosis, myopathy, Mechanisms of GC action
from effects on primary and second- atherosclerosis, and hypertension (8, Both the desirable and unwanted GC ef-
ary immune cells. The inflammatory 18, 19). Other adverse effects include fects depend on the structure of the GC

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 Pharmacodynamics of glucocorticoids / C. Strehl et al.

molecule which belongs to the family Genomic effects are mediated by dissociation of the cGCR multi pro-
of steroid hormones and is character- the cytosolic GCR (cGCR) tein complex, and
ised by a sterol skeleton. A number of Glucocorticoids are lipophilic mole- • Specific interactions with a mem-
empirical studies over many years have cules, which easily pass through plasma brane-bound GCR (mGCR).
established that the 17-hydroxy, 21-car- membranes. The glucocorticoid recep- These non-genomic effects are con-
bon steroid configuration is required for tor complex, consisting of different sidered to be clinically important at
glucocorticoid activity through bind- proteins (29, 30, 32), is found in the high, very high or pulse doses (pred-
ing to the glucocorticoid receptor (22). cytoplasm. Since the first detection of nisone-equivalent >30 mg per day (20).
Changes in this structure can result in the GCR in 1985 (34), a large number At high dosages, GC concentrations
an increase or decrease of specific phar- of receptor variants has been described, are achieved which can significantly
macodynamic characteristics. comprising different lengths of the ami- change the physicochemical properties
Enhancement of glucocorticoid activity no-terminus depending on the starting of biological membranes, especially
by variations near the C11 atom leads point of translation (35) and different plasma and mitochondrial membranes,
to increased desirable clinical effects, post-translational modifications (such resulting in a modification of func-
such as in as phosphorylation or sumoylation) that tion and activity of membrane-associ-
• Prednisolone, in which a double affect the levels of transcriptional activ- ated proteins (21, 31). Furthermore,
bond is inserted between C1 and ity (36, 37). in immune cells, calcium and sodium
C2, After binding of the GC to the gluco- cycling across the plasma membranes
• Triamcinolone, in which a halogen corticoid receptor complex with high is reduced, which in part may account
is included, and affinity, the proteins dissociate from for immunosuppression and reduction
• Methylprednisolone or dexametha- the complex (30) and the GC/cGCR of inflammation (31). ATP produc-
sone, both of which are expanded by complex translocates into the nucle- tion, which is essential to immune cells
a methyl or fluoro-group (23). us. There it is able to bind to specific (e.g. for cytokine synthesis, migration,
Adverse effects may be minimised by DNA binding-sites (30), resulting in phagocytosis, antigen processing and
a reduction of the mineralocorticoid an induced synthesis of anti-inflam- presentation) also is diminished by in-
activity of GCs via variations near matory and regulator proteins (“trans- hibiting oxidative phosphorylation and
the C18 atom (e.g. methylation or hy- activation”, as described above) (2). increasing the mitochondrial proton
droxylation) (23). GCs with an 11-keto Furthermore, monomers of the GC/ leak (45).
instead of an 11-hydroxy group, such cGCR complex directly or interact in- The second class of non-genomic ef-
as cortisone and prednisone, are pro- directly with transcription factors (via fects is mediated by proteins which dis-
hormones that must be reduced in the “transrepression”, as described above) sociate from cGCR-multiprotein com-
liver to their 11-hydroxy configurations which are involved in the regulation plex after binding of GCs to its recep-
(22). Cortisone is converted by hepatic of the expression of pro-inflammatory tor. Proteins, such as the co-chaperon
pathways to cortisol, and prednisone is proteins (e.g. IL-1, IL-2, IL-6, TNF-α, Src, heat-shock proteins (e.g. Hsp90,
converted to prednisolone, in order to Interferon γ (IFN-γ)) (2, 12, 13, 38- Hsp70, Hsp56 and Hsp40), immunophi-
become biologically active (22). 40). lins and kinases of the mitogen-activat-
New insights into the mechanisms of ed protein kinase (MAPK) signalling
GC action suggest that endogenous Rapid, non-genomic effects of system are thought to mediate some
glucocorticoids are subject to extensive glucocorticoids of the rapid effects of glucocorticoids
pre-receptor metabolism within target Over the years, effects were recognised (42, 46). Glucocorticoids inhibit the re-
cells or tissues (24). 11β-hydroxys- which occur too quickly to be medi- lease of arachidonic acid, an essential
teroid dehydrogenases (11β-HSDs) ated by the above-mentioned genomic mediator of cell growth and several
change the balance between active and mechanism of GC action. Typically, metabolic/inflammatory reactions. This
inactive glucocorticoids (24, 25). Thus, significant changes on cellular, tissue inhibition of arachidonic acid release
11 β-HSD type 1 catalyses the forma- or organism level become evident after can be blocked by the glucocorticoid
tion of active cortisol from cortisone, hours or days, but if GCs were given antagonist RU486 but is insensitive to
whereas 11β-HSD type 2 inactivates intravenously or intra-articularly at a actinomycin D (42, 45). These obser-
active glucocorticoids, these processes high dose, rapid clinical effects have vations imply that arachidonic acid re-
being influenced by local inflammation been observed. These anti-inflamma- lease is not dependent on transcription;
(24, 26, 27). Of note, the solubility, the tory and immunosuppressive effects, hence, the cGCR does not only mediate
half-life in the plasma and the affinity also called rapid, non-genomic effects, genomic effects, but is also involved in
to its receptor also influence the phar- have been considered to be classifiable rapid, non-genomic GC actions.
macodynamics of glucocorticoids (23). into three mechanisms of GC action The third possibility of non-genomic
All effects of glucocorticoids are me- (31, 41-44): GC effects is the specific interaction
diated by genomic and non-genomic • Non-specific interactions of gluco- with membrane-bound glucocorticoid
mechanisms of action (10, 11, 21, 28- corticoids with cellular membranes, receptors (mGCR), the existence of
33). • Non-genomic effects mediated by which was first described in amphib-

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Pharmacodynamics of glucocorticoids / C. Strehl et al.

Table I. Immunostimulatory effects of glucocorticoids. tion in more detail, and for clinicians
to appreciate important differences be-
Effect References
tween low versus high doses of gluco-
Enhancement of IgG synthesis (66) corticoids, administered with optimal
Enhancement of nitric oxide (NO) secretion (67) recognition of chronobiology (see arti-
Enhancement of pro-inflammatory cytokine secretion, such as IL-1β, (63, 67-74) cle in this supplement by Spies).
TNF-α, IL-6, macrophage inhibitory factor (MIF)
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