The Role of Interleukin-6 in the Pathogenesis, Prognosis and Treatment of Severe COVID-19

Abstract

: A newly identified virus appeared in Wuhan, China, in December 2019, was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and causes the coronavirus disease 2019 (COVID-19). SARS-CoV-2 presents similarities with two previous coronavirus pandemics, MERS (Middle East Respiratory Syndrome) and SARS-CoV, concerning phylogenetic origin, structural composition, and clinical symptoms, thus, leading to common pathogenic mechanisms. The purpose of this review is to declare the role of interleukin-6 (IL-6) in the pathogenesis, prognosis, and treatment of COVID-19 by comparing its effect on SARS-CoV and MERS cases. Increased levels of IL-6 comprise the key for the stimulation of cytokine storm and the progression of SARS, MERS, and COVID-19 cases. Especially, in COVID-19 patients, the overactivation of NF-kΒ, which is caused by the binding of coronavirus spike protein S to alveolar epithelial cells, up-regulates IL-6 and promotes its systematic circulation, causing alveolar damage and extrapulmonary injury. Additionally, IL-6 can be used to evaluate respiratory failure and identify asymptomatic patients. Tocilizumab (TCZ), a monoclonal antibody which blocks IL-6 signaling, comprises a remedial option against COVID-19. TCZ improves oxygenation, reduces fever, and decreases levels of IL-6. IL-6 plays a major role in the pathogenesis of cytokine storm and the progression of COVID-19 and may be used as a therapeutic target against COVID-19. However, further research is needed concerning the relation of IL-6 in COVID-19 cases and more clinical trials are required to declare TCZ as a treatment option.

Vitamin D Inhibits IL-6 Pro-Atherothrombotic Effects in Human Endothelial Cells: A Potential Mechanism for Protection against COVID-19 Infection?

“…Thus, it is conceivable that COVID-19 might promote thrombotic events by this NF-kB mediated pathway. In line with previous observations [31], in the present report we show that IL-6, one of the key cytokines of the COVID inflammatory storm, increases translocation of NF-κB to the nucleus as well as activation of STAT3. It is known that the induction of such an inflammatory process in the host cell is often associated the engagement of inflammasomes, which are protein platforms that aggregate in the cytosol in response to different stimuli [36].…”

“…Specifically, in the COVID-19 infection, the viral attack to the host causes a maladaptive immunological response that increases vascular permeability, finally leading to endothelial dysfunction and activation of coagulation [29,30]. In this host response, which involves several immunological cells and the release of several cytokines, COVID-19 infection is associated with a cytokine storm in which IL-6 levels are strongly increased, especially in those critical patients in which thrombosis is enhanced [11,31]. Here, we have demonstrated that IL-6 exerts prothrombotic effects on human endothelial cells because it promotes expression of functional TF, suggesting that this might be one of the possible mechanisms by which COVID-19 causes thrombosis.…”

Alterations in cortisol and interleukin-6 secretion in patients with COVID-19 suggestive of neuroendocrine-immune adaptations

“…Interleukin-6 (IL-6) is a pleiotropic proin ammatory cytokine which regulates the acute phase in ammatory response and plays a central role in immune-mediated diseases, being a therapeutic target in various in ammatory conditions [11][12][13]. Several lines of evidence supported a potential prognostic role for IL-6 for severe outcomes in hospitalized COVID-19 patients, showing that high IL-6 serum levels at admission predicted the development of hypoxemia requiring hospitalization [14][15][16][17]. IL-6 may also affect the function of endocrine tissues including stimulation of the hypothalamic-pituitary-adrenal (HPA) axis in healthy volunteers [18] and patients with sepsis [19] and cancer [20][21][22].…”

Biomarkers during COVID-19: Mechanisms of Change and Implications for Patient Outcomes

“…The relationship between interleukin-6 and COVID-19 severity has been investigated by many studies [ 17 , 18 , 19 ]. Interleukin-6 (IL-6), a cytokine secreted by stimulated monocytes and macrophages, mediates a broad range of biological reactions [ 20 ].…”