STUDY. Newer types of steroidal anti-inflammatories may have fewer side effects. Mechanisms of action of cortisone, elucidated

A recent study published in the journal Nature sheds new light on how cortisone inhibits inflammation, offering insights into the development of anti-inflammatory agents with less severe side effects.

Synthetic derivatives of glucocorticoids are developed to reduce inflammation and are used for the treatment of many immune-mediated inflammatory diseases. These are among the most commonly used drugs.

Cortisone, along with other glucocorticoids are recognized for their effectiveness in reducing excessive immune reactions. However, to date, the exact mechanisms by which it acts have not been fully understood. The team of researchers from Charité – Universitätsmedizin Berlin and Uniklinikum Erlangen investigated the potential mechanisms in detail, revealing that glucocorticoids can reprogram immune cell metabolismthus activating natural inflammation blocking mechanisms. These findings may lead to the development of anti-inflammatory agents with fewer adverse effects.

In search of safer alternatives, the research team conducted a detailed study of exactly how glucocorticoids act on the immune system. They found that it not only influences gene expression in immune cells, but also has a significant effect on cellular metabolism, particularly at the level of mitochondria, having a major role in reversing the changes initiated by inflammatory stimuli. This reprogramming of cellular metabolism is crucial for the anti-inflammatory effects of glucocorticoids. Their observations showed that when macrophages are activated to fight a pathogen, the mitochondria change their function, producing the substances needed to fight the foreign agent. Glucocorticoids reverse this reaction, helping to calm inflammation and restore balance in the body.

In the study, the researchers focused in particular on macrophages, the immune cells responsible for removing foreign particles from the body. These cells play an essential role in the development of inflammatory diseases. An interesting aspect of the study was the role of itaconate, a small molecule with anti-inflammatory properties, produced by macrophages during inflammatory reactions. Itaconate is produced early by activated macrophages, but is useful in short-term inflammation. Glucocorticoids have been shown to exert their anti-inflammatory effect through stimulation of itaconate production in immune cellsalso interfering with the production of pro-inflammatory cytokines and thus restoring the balance in the chronic inflammatory response.

“When there is a persistent inflammatory stimulus, the decrease in itaconate production is a problem, because then there is no longer a ‘brake’ on the immune system, even if it is working at full capacity, possibly leading to chronic inflammation. This is where glucocorticoids come in. By reprogramming mitochondrial function, they intensify the formation of itaconate in macrophages, restoring its anti-inflammatory effect,” explained Dr. Jean-Philippe Auger, scientist at Uniklinikum Erlangem, lead author of the study, in an article published in Charité.

Cortisol and cortisone are steroid hormones produced in the adrenal gland. Cortisol, often called the “stress hormone”, is essential for regulating metabolism, controlling blood sugar levels, reducing inflammation. This is the biologically active form, influencing various body systems, including the immune and cardiovascular systems, and helps the body respond to stress.

Cortisone is a metabolite of cortisol, produced by the action of an enzyme, and is considered biologically inactive until it is converted back to cortisol in the liver. Synthetic forms of both hormones are used in medicine for various applications. In addition to its role in sugar and fat metabolism, cortisone also influences a number of other physiological parameters, such as blood pressure, heart rate and respiration. At higher doses, its secretion leads to the inhibition of the activity of the immune system, being useful in the treatment of inflammatory and autoimmune diseases. However, side effects of cortisone, such as high blood pressure, osteoporosis, diabetes, and weight gain, limit its long-term use.

Itaconate is a metabolite secreted by macrophages in immune responses, which has strong immunomodulatory effects and which has anti-inflammatory and antioxidant properties in case of certain diseases.

However, although itaconate appears to be key in understanding anti-inflammatory mechanisms, its use as a drug is currently not feasible due to its high instability and reactivity. Therefore, researchers are now turning their attention to discovering synthetic compounds that can reprogram mitochondrial metabolism in immune cells while having less severe side effects.

In conclusion, this study represents an important step in understanding how cortisone and glucocorticoids in general act on the immune system. Their findings could open new directions for the development of safer anti-inflammatory therapies with fewer side effects.

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