How do glucocorticoids help in regulating inflammation?

From the Guidelines

Glucocorticoids are highly effective in regulating inflammation through multiple mechanisms, including inhibiting pro-inflammatory cytokines, reducing inflammatory cell migration, and suppressing T-cell activation, as evidenced by the most recent study 1.

Mechanisms of Action

Glucocorticoids 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. They inhibit the production of pro-inflammatory cytokines like IL-1, IL-6, and TNF-α while increasing anti-inflammatory proteins.

• They reduce the migration of inflammatory cells to sites of inflammation by decreasing the expression of adhesion molecules and chemokines.
• Glucocorticoids also stabilize lysosomal membranes, preventing the release of inflammatory enzymes, and inhibit phospholipase A2, which reduces the production of inflammatory mediators like prostaglandins and leukotrienes.
• Additionally, they suppress T-cell activation and proliferation, further dampening the immune response.

Clinical Use and Monitoring

Common glucocorticoid medications include prednisone (typically 5-60 mg daily), methylprednisolone, dexamethasone, and hydrocortisone, with dosages varying based on the condition being treated.

• While effective for acute inflammatory conditions, long-term use requires careful monitoring due to potential side effects including osteoporosis, hyperglycemia, hypertension, and adrenal suppression, as highlighted in 1.
• The use of the lowest dose possible is recommended, as stated in 1, to minimize adverse effects.
• In certain conditions like ARDS, methylprednisolone may be considered in specific doses and durations, as suggested in 1, to improve outcomes.

Evidence and Recommendations

The most recent and highest quality evidence supports the use of glucocorticoids in specific clinical scenarios, such as early and late ARDS, with careful consideration of the dose and duration of treatment, as outlined in 1.

• The evidence also emphasizes the importance of patient monitoring and the management of potential side effects to ensure the safe and effective use of glucocorticoids, as discussed in 1, 1, and 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

Mechanisms of Glucocorticoid-Induced Inflammation Regulation

• 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 Applications of Glucocorticoids

• GCs constitute a first-line treatment for many autoimmune and inflammatory diseases, including rheumatoid arthritis, due to their potent anti-inflammatory and immunosuppressive actions 4.
• GCs are also used to treat other inflammatory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), allergies, multiple sclerosis, tendinitis, lupus, atopic dermatitis, ulcerative colitis, and osteoarthritis 5.
• However, the long-term use of GCs is associated with many side effects, including osteoporosis, metabolic, gastrointestinal, and cardiovascular side effects 4, 6.

Future Directions

• Research is ongoing to develop novel GCs with reduced side effects and minimal toxicity, which could lead to improved treatment options for inflammatory and autoimmune diseases 4, 3, 5.
• A better understanding of the mechanisms of GC action could also lead to the development of new anti-inflammatory therapies that target specific transcription factors, such as nuclear factor-kappa B 3.