Nearly two years after the lethal pandemic of COVID-19, which is considered a joker virus that may bypasses many immune defenses in our bodies such as innate and adaptive immunity, with all types of cells, there are important markers at the long road for treatment, such as interleukin (Il-6), neutrophils, high ferritin, and high D dimer. Additionally, post COVID-19 or long COVID-19 effects include neuropsychiatric problems such as smell dysfunctions and hormonal dysfunctions. Therefore, this article will highlight the adrenal gland as a place where the immune and endocrine systems meet. Additionally, dexamethasone has no effect on Il-6 secreted from the adrenal cortex, which allows Il-6 to be produced during stress. We need a new classification of IL-6 at physiological and pathological aspects, as the stimulatory factors are different. Endocrine Il-6 is stimulated by ACTH, but immune Il-6 is stimulated by il-1β and angiotensin II. Of note, dexamethasone saves critically COVID-19 patients but has no effect on Il-6 of endocrine origin, either basal or stimulated. Therefore, the adrenal gland serves as a vital link between the endocrine and immunological systems the pathogenesis of COVID-19.The importance of synergistic actions of cytokines in HPA axis stimulation has been demonstrated by several studies. Viruses that induce early, innate NK cell-mediated anti-viral defenses, characterized by early proinflammatory cytokine production, cellular infiltration, and inflammation, tend to produce early glucocorticoid responses, thereby protecting the host from pro inflammatory cytokine-mediated pathology. Viral infections, in general, are physiologically stressful, as indicated by the concomitant activation of the HPA axis. That substances released from the adrenal gland could affect immune function was one of the initial indications that there are meaningful interactions between the neuroendocrine and immune systems In addition, Il-6 is the key sex-linked variation in immune responses. by molecular docking Binding interaction dexamethasone with interleukin6. It shows binding affinity was found -6.7 Kcal/mol