How do glucocorticoids help in regulating inflammation?

From the Guidelines

Glucocorticoids are highly effective in regulating inflammation by suppressing the inflammatory response through multiple mechanisms, including inhibiting pro-inflammatory cytokines and reducing the recruitment of inflammatory cells. These steroid hormones bind to glucocorticoid receptors in the cytoplasm of cells, forming complexes that move into the nucleus where they interact with DNA to alter gene expression 1. The mechanisms by which glucocorticoids regulate inflammation include:

• Inhibiting the production of pro-inflammatory cytokines like interleukin-1, interleukin-6, and tumor necrosis factor-alpha
• Increasing anti-inflammatory proteins
• Reducing the recruitment of inflammatory cells such as neutrophils and monocytes to sites of inflammation by decreasing the expression of adhesion molecules
• Stabilizing lysosomal membranes, preventing the release of destructive enzymes
• Inhibiting phospholipase A2, which reduces the production of inflammatory mediators like prostaglandins and leukotrienes Common glucocorticoid medications include prednisone (typically 5-60 mg daily), methylprednisolone, dexamethasone, and hydrocortisone, with dosages varying based on the condition being treated 1. However, long-term use of glucocorticoids requires careful monitoring due to potential side effects like osteoporosis, hyperglycemia, and adrenal suppression, and the lowest dose possible should be used 1. In patients with axial disease, systemic glucocorticoids should not be used long-term, but short-term high-dose glucocorticoids may have a modest effect on signs and symptoms 1. Additionally, glucocorticoids can affect body weight, with a dose-response relationship and increased risk of weight gain with higher doses and longer duration of treatment 1. In critically ill patients, methylprednisolone may be considered in patients with early or late persistent ARDS, with a dose of 1 mg/kg/day or 2 mg/kg/day, respectively, followed by slow tapering over 13 days 1.

From the FDA Drug Label

CLINICAL PHARMACOLOGY Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.

Glucocorticoids help in regulating inflammation by having potent anti-inflammatory effects. They achieve this by modifying the body's immune responses to various stimuli.

• The exact mechanism of how glucocorticoids regulate inflammation is not explicitly stated in the label. 2

From the Research

Mechanism of Glucocorticoids in Regulating Inflammation

• Glucocorticoids (GCs) are widely used for the suppression of inflammation in chronic inflammatory diseases, and their anti-inflammatory actions are mediated by several mechanisms 3.
• GCs bind to glucocorticoid receptors in the cytoplasm, which then dimerize and translocate to the nucleus, where they bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, resulting in increased transcription 3.
• The most striking effect of GCs is to inhibit the expression of multiple inflammatory genes, including cytokines, enzymes, receptors, and adhesion molecules, which is likely due to a direct inhibitory interaction between activated glucocorticoid receptors and activated transcription factors 3.
• GCs also change the chromatin structure by interacting with CREB-binding protein (CBP), which acts as a co-activator of transcription, and may lead to deacetylation of histone, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites, thereby suppressing gene expression 3.

Clinical Use of Glucocorticoids

• GCs constitute a first-line treatment for many autoimmune and inflammatory diseases, and are added frequently to disease-modifying antirheumatic drugs (DMARDs) in various arthritic diseases, such as rheumatoid arthritis 4.
• GCs are the mainstay treatment of a variety of inflammatory and autoimmune disorders, but their use is often limited by metabolic side effects, drug interactions, and adverse reactions 5.
• The goal of treatment with GCs is to monitor the broad spectrum of side effects and to improve the risk/benefit ratio of GC therapy, which can be achieved by targeting glucocorticoid pre-receptor metabolism for metabolic and inflammatory diseases 6.

Novel Anti-Inflammatory Modes of Action

• New insights into the novel anti-inflammatory mode of action of GCs have been discovered, which may lead to the development of novel anti-inflammatory drugs with reduced side effects and minimal toxicity 7.
• The anti-inflammatory and immunosuppressive effects of GCs are usually mediated by transrepression mechanism, whereas the metabolic and toxic effects are usually manifested by transactivation mechanism 7.
• Several research studies are rising to comprehend the mechanisms of GC resistance, which would be helpful in improving the GC resistance in asthma and COPD patients 7.