Corticosteroid formulations are usually prescribed to treat acute inflammations, often related to sports injury, repetitive strain injury, or knee pain. Medications containing cortisone or derived from it are also used to treat chronic inflammatory illnesses such asthma, diabetes, and chronic inflammatory bowel diseases. This is due to the quick anti-inflammatory impact that these medications typically have.
But there are disadvantages as well: Their therapeutic effectiveness is frequently time-limited since they are effective initially but lose some of their positive effects as treatment goes on. There may also be major adverse reactions, such as osteoporosis, heightened susceptibility to infections, stomach ulcers, and metabolic problems.
“When using these preparations, it’s therefore important to limit and optimize their use,” says Prof. Oliver Werz, Professor for Pharmaceutical/Medicinal Chemistry at the University of Jena.
But what is the most effective time to start treatment, and when should you avoid using corticosteroid medications? This question has not yet had a conclusive response.
In a recent study, Prof. Werz and Dr. Markus Werner of the Institute of Pharmacy, along with researchers from the University of Jena, Jena University Hospital, and Harvard Medical School (U.S.), have now clarified a crucial biochemical mechanism describing how cortisone preparations regulate inflammation-resolving effects in human immune cells, paving the way for effective use of these medications. In PNAS, the researchers report their findings.
Cortisol Affects Enzyme Activity
Pro-inflammatory immune cells—including M1 macrophages—appear first during an inflammatory reaction. Prostaglandins and leukotrienes – the pro-inflammatory messenger chemicals, are produced by them and cause typical symptoms like pain and fever. The second phase occurs after a few days, during which the inflammation diminishes. At that time, “M2” type macrophages become more active and start releasing messengers (i.e., resolvins) that help to reduce inflammation.
“In studies on cell cultures, we were able to show that cortisone regulates the activity of certain enzyme genes in the immune cells, which influence the inflammatory process,” explains Dr. Werner. In this approach, the early-appearing M1 macrophages are induced to produce inflammation-resolving resolvins, whereas the later-appearing M2 macrophages were severely impaired due to cortisone.
The 15-lipoxygenase enzymes, which exist in two different forms in the immune cells – 15-lipoxygenase-1 and 15-lipoxygenase-2, control this impact. “We found that cortisone upregulates 15-lipoxygenase-2 in pro-inflammatory M1 macrophages of the early inflammatory phase. This enzyme catalyzes the formation of resolvins, thereby stopping and resolving inflammatory processes, which is partly responsible for the positive effects of cortisone,” says Dr. Werner.
The trials also show that cortisone effectively “switches off” 15-lipoxygenase-1 to decrease the production of resolvin in inflammation-resolving M2 macrophages, essential for healing. “This explains why the use of cortisone in the later phase of inflammatory diseases no longer leads to symptom relief, and can even be counterproductive and inhibit regeneration processes,” adds Prof. Werz.
From Bench to Bedside
The effects were demonstrated in subsequent investigations using immune cells from patient specimens once the researchers had uncovered the mechanisms at the level of gene regulation. Patients at Jena University Hospital with chronic inflammatory conditions, including Crohn’s disease and ulcerative colitis, were among them, as were those who had significant acute inflammation brought on by COVID-19 and were given corticosteroid medications. These patients’ blood samples were taken before and after the drug was administered, and they had their enzyme activity and inflammatory characteristics measured.
“As in the experiments on cell cultures, we were able to detect a clear upregulation of 15-lipoxygenase-2 in the patient groups treated with cortisone,” reports Dr. Benjamin Giszas, a doctor at the Clinic for Internal Medicine IV. Giszas supervised the studies as part of his Clinician Scientist project.
The results suggest, in the opinion of the researchers, that the treatment of inflammatory illnesses could be enhanced by a time-limited use of cortisone and by novel 15-lipoxygenase-based therapy principles, with less cortisone-related adverse effects.
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