Dexamethasone, Interleukin 6, and the Adrenal Gland are the Real Battles for COVID-19: Our Molecular Docking, Physiological, and Immunological Explanations of Why the Clinical Benefit of Dexamethasone is More Evident in Males

More than two years have passed since the pandemic and despite all the efforts of researchers, the pathogenesis of the SARS-CoV-2 has not yet been resolved. The SARS-CoV-2 coronavirus that causes COVID-19 has high ability of mutation resulting in different variants of the virus. This mutation helps the virus bypass the body's immune defenses such as innate and adaptive immunity. Interleukin (Il-6), neutrophils, high ferritin, and high D dimer are crucial markers for all sorts of cells on the lengthy path to treatment of COVID-19. IL-6 is one of the key mediators of inflammation and viral cytokine storm in COVID-19 patients. In humans, interleukin (IL)-6 is a strong stimulator of the hypothalamic-pituitary-adrenal (HPA) axis at all levels, and it appears to have a pathogenic role in chronic stress and physiological aging. The adrenal glands have earned further recognition as key modulators of immune function, because secretory products of the adrenal glands. Dexamethasone inhibits TNF-α–induced IL-6 mRNA expression and protein secretion by reducing IL-6 mRNA stability. Although Dexamethasone provides benefits in patients with coronavirus disease but there is sex linked difference between male and female at response to this drug. It was showed that this drug might indeed have an effect in treating covid-19 but the clinical benefit of dexamethasone is more evident in males. Here we propose a testable hypothesis that dexamethasone may be effective in men better than female owing to two factors the first is the ability of males to induce high secretion of adrenal hormone under stress vs female. In males both stressors induced a significant increase, whereas in female adrenal e excretion remained on the same level under the two stress conditions. Both Adrenal e hormones and dexamethasone are hypothesized to promote blood neutrophil levels by increasing neutrophil exit from bone marrow, delaying neutrophil outflow from circulation, and lengthening the half-life of circulating neutrophils. Neutrophils a type of white blood cells that can downregulate interferon-stimulated genes, i.e., suppress their activity. When male patients received the steroid treatment, the dysregulated interferon signals went away quickly. But in female patients, the proportions of neutrophils were not as high and they did not react to the steroids in the same way. The second factor is that ACTH response to il-6 is stronger in males than females and ACTH was found to induce il-6. Therefore, male interact with dexamethasone better than females. Additionally, dexamethasone does not affect Il-6 secreted from the adrenal cortex, which allows Il-6 to be produced during stress and increase neutrophil ratio leading to stronger response in males. We need a new classification of IL-6 at physiological and pathological aspects, as the stimulatory factors are different. it was found that ACTH is h Endocrine Il-6 is stimulated by ACTH, but immune Il-6 is stimulated by il-1β and angiotensin II. Of note, dexamethasone critically saves COVID-19 patients but has no effect on Il-6 of endocrine (ACTH stimulated) origin, either basal or stimulated. We studied the molecular docking of dexamethasone with interleukin-6 and showed that the binding interaction of dexamethasone with interleukin-6 was with high binding affinity (-6.7 Kcal/mol)