For the past few tutorials we have been learning about drugs that deal with inflammation and
the immune response. Let’s continue by discussing glucocorticoids, a drug class
pertaining to inflammation and autoimmune disease. Glucocorticoids are a class of corticosteroid.
These are hormones that are endogenously produced in the adrenal cortex of the adrenal gland,
but they are also sometimes given therapeutically through exogenous pharmacological deployment.
The endogenous glucocorticoid is cortisol, but for more favorable pharmacology,
synthetic alternatives are often used instead. These include: prednisolone, hydrocortisone,
dexamethasone, and beclomethasone dipropionate, though there are many more.
Glucocorticoid primary functions are to be immune suppressive and anti-inflammatory.
With this in mind, it is quite straightforward to understand
they have therapeutic efficacy in most autoimmune and inflammatory diseases.
The most common conditions that glucocorticoids treat include asthma, polymyalgia rheumatica,
chronic obstructive pulmonary disease, and rheumatoid arthritis. It’s important to note
there are a large number of other conditions for which glucocorticoids are an approved treatment.
Depending on what condition the glucocorticoid is intended to treat, different drugs in this
class and different routes of administration are possible. Of course, to limit off-target effects,
local administration is always preferred, if possible. This is especially true for drugs
that induce widespread systemic effects, like glucocorticoids. A good example of a treatment
protocol like this is the use of inhalators in the local delivery of beclomethasone, a synthetic
glucocorticoid, directly to the airways for the treatment of inflammation caused by asthma.
In systemic conditions, oral use of drugs such as prednisolone, and intravenous use of drugs
such as dexamethasone are sometimes utilized. A discussion of every inflammatory disease and their
specific treatment protocols is beyond the scope of this tutorial, so let’s focus on describing the
general mechanism of action of all drugs in this family, and how it leads to therapeutic outcomes.
Glucocorticoids mediate their efficacy through the glucocorticoid receptor, also sometimes
referred to as nuclear receptor subfamily 3 group C member 1, or the NR3C1 receptor.
As this name suggests, the glucocorticoid receptor is a nuclear receptor, which means that drugs in
the glucocorticoid family must traverse the plasma membrane in order to reach their target receptor.
The glucocorticoid receptor without any drug bound exists predominately in the cytosol,
bound to a complex of chaperone proteins, hsp90, hsp70, and p23.
Following spontaneous diffusion into the cytosol, glucocorticoids bind to the cytosolic receptor.
Upon drug-receptor binding and activation, the glucocorticoid receptor is phosphorylated,
and the chaperone proteins dissociate. The activated form of the receptor complex exhibits
both non-genomic and genomic signaling. Non-genomic signaling occurs with the
activated glucocorticoid in the cytosol, where it inhibits PI3K, Akt, and MAPK
activity since these pathways are associated with increased cell growth and proliferation.
Glucocorticoids are also used in the treatment of certain cancers,
and this will be covered in more detail in later tutorials on anti-cancer chemotherapies.
However, the predominant mechanism of action for glucocorticoids is through genomic signaling
via the modulation of gene expression. The activated drug-receptor complex undergoes
translocation into the nucleus via the nuclear pore complex, or NPC, which is a large pore
protein that controls transit of many molecules into and out of the nucleus. Following passage
into the nucleus, the drug-receptor complex alters gene expression, much like most nuclear receptors.
This is done via three mechanisms, those being direct, tethering, and composite.
First, the direct mechanism utilizes glucocorticoid response elements, where
the drug-receptor complex specifically binds to these response elements on DNA. With the tethering
mechanism, the drug-receptor complex binds to other DNA-bound transcription factors. And third,
the composite mechanism can be conceptualized as a mix of the direct and tethering mechanisms.
The drug-receptor complex binds to glucocorticoid response elements, which can subsequently bind to
other transcription factors, that are in turn bound to their respective response elements.
Glucocorticoids can increase the expression of certain genes,
known as trans-activation, or reduce the expression of genes, known as trans-repression.
Considering the ubiquitous expression of the glucocorticoid receptor in most cell types
with different protein expression repertoires, alongside the fact that glucocorticoids can
influence the expression of 10-20% of the human genome, it can be appreciated how
vast and complicated the pharmacodynamic profile is for drugs of this class. In this tutorial,
we will focus on a few mechanisms that are thought to have been the most substantiated
to lead to the desired clinical outcomes of reducing inflammation and immunosuppression.
First, let’s focus on reducing inflammation. Glucocorticoids decrease the gene expression of
cyclooxygenase, or COX enzymes, which we learned about when we covered NSAIDs. This
reduces the production of prostaglandins and other eicosanoids that cause inflammation.
Glucocorticoids increase the expression of lipocortin,
which inhibits PLA2, thus reducing the liberation of arachidonic acid from the plasma membrane.
This further reduces the enzymatic turnover of COX to produce pro-inflammatory prostaglandins,
since arachidonic acid is a key substrate for this enzymatic reaction.
Second, let’s examine immunosuppressive effects. A main mechanistic driver is
thought to arise from the glucocorticoid drug-receptor complex displacing another
transcription factor called nuclear factor kappa-light-chain-enhancer of activated B cells,
almost always shortened to NF-κB. NF-κB, as we discussed in the immunology series,
is an important transcription factor that has numerous pro-immune, and pro-inflammatory effects.
For example, NF-κB increases the expression of genes encoding cytokines such as interleukins
and tumor necrosis factor alpha, or TNF-α, which induce maturation of T-cells,
increase their activation, and have important pro-inflammatory effects.
Given that glucocorticoids inhibit the efficiency of NF-κB to act as a transcription factor, it is
quite easy to appreciate the anti-inflammatory and immunosuppressive effects drugs of this
class have. It’s worth bearing in mind that we are just scratching the surface on the diverse
signaling cascade the glucocorticoids are involved in, as we are discussing only the
most important signaling mechanisms. Due to the immunosuppressive effects
that glucocorticoids have, the propensity for infection from both readily infectious
and opportunistic pathogens is considerably increased, and this is a key side effect.
Infection can be managed by using the lowest dose possible that is capable of achieving the
desired therapeutic effect, and the shortest time course of drug exposure that is possible.
Much like many physiologically homeostatic variables, equilibrium is key. In this instance,
using glucocorticoids to pharmacologically modulate immunosuppression and inflammation
needs to be carefully balanced. If levels are too low, sufferers from autoimmune and inflammatory
diseases won’t receive enough immunological and inflammatory inhibition. If too high for too long,
the risk of infection will be too high. Other notable side effects include raised
concentrations of plasma glucose, cholesterol, and triglyceride, due to the increased
transcription of gluconeogenic proteins. Glucocorticoids also impair wound healing
because some aspects of the inflammatory and immune systems are required for wound healing.
Excessive long-term use of glucocorticoids can also lead to Cushing’s syndrome.
Usually, this syndrome manifests as a result of increased production of cortisol, the endogenous
agonist for the glucocorticoid receptor, which again is synthesised in the adrenal cortex.
Cushing’s syndrome causes face rounding, weight gain with associated increase in body fat,
thinner skin, increased risk of bruising, bone weakness, high blood pressure, and depression.
In conclusion, exogenous glucocorticoids are powerful anti-inflammatory and immunosuppressive
pharmacological agents that influence most cell types, primarily through the modulation of gene
transcription, though they also have important influences on non-genomic signaling pathways.
However, much like many physiological parameters that are modulated homeostatically,
an appropriate balance must be struck between inflammation and anti-inflammation as well as
immunosuppression and normal immunological function, in order to maintain good health.