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Emerging data suggest that many patients infected with COVID-19 may die due to an excessive response of their immune system, characterized by the abnormal release of circulating cytokines, termed cytokine release syndrome (CRS). CRS plays a major role in the deterioration of COVID-19 patients, from pneumonia through acute respiratory distress syndrome (ARDS), cumulating in systemic inflammation and ultimately multi-system organ failure. This phenomenon of a plethora of cytokines wreaking havoc throughout the body is often vividly referred to as “cytokine storm.”
Many cytokines take part in the “cytokine storm” in COVID-19 patients, including IL-6, IL-1, IL-2, IL-10, TNF-α and IFN-γ; however, a crucial role seems to be played by IL-6, whose increased levels in the serum have been correlated with respiratory failure, ARDS, and adverse clinical outcomes.
IL-6 has significant pro-inflammatory properties, and it functions through two main signaling pathways: cis or trans. In cis signaling, IL-6 forms a complex with the membrane-bound IL-6 receptor (mIL-6R) and gp130 which then activates downstream the Janus kinases (JAKs) and signal transducer and activator of transcription 3 (STAT3). The activation of this signal cascade leads to pleiotropic effects on the acquired immune system (B and T cells) as well as the innate immune system (neutrophils, macrophages, and natural killer cells) which can contribute to CRS. In trans signaling, high circulating IL-6 concentrations bind to the soluble form of IL-6 receptor (sIL-6R) and form a complex with a gp130 dimer on most somatic cell types. The resultant IL-6–sIL-6R–JAK-STAT3 signaling is then activated in cells that do not express mIL-6R, such as endothelial cells. This severely aggravates the “cytokine storm” through secretion of vascular endothelial growth factor (VEGF), monocyte chemoattractant protein–1 (MCP-1), IL-8, and additional IL-6, as well as reduced E-cadherin expression on endothelial cells. Secretion of VEGF and reduction of E-cadherin expression contribute to vascular permeability and leakage which participate in the pathophysiology of hypotension and pulmonary dysfunction in ARDS.
Previous studies have demonstrated the efficacy of IL-6–IL-6R antagonists for the treatment of CRS and secondary hemophagocytic lymphohistiocytosis (sHLH) which both feature serum cytokine upregulation. This suggests a crucial role for IL-6 in the pathophysiology of cytokine-driven hyperinflammatory syndromes and classifies IL-6 as a potential target for COVID-19 targeted therapy. In fact, IL-6 and IL-6R antagonists are under way for clinical trials for the management of COVID-19 patients with severe respiratory complications.
All this evidence highlights the importance of the “cytokine storm” and particularly IL-6 and its downstream signaling pathways in COVID-19 disease. An accurate detection and monitoring of all those components are crucial for a better understanding of the disease progression and for assessing the therapeutic response. Enzo offers a plethora of products that would help the scientific communities in tackling these challenges, including our IL-6 (human) High Sensitivity ELISA kit and many other cytokine ELISA assays. Additionally, we provide a list of antibodies, recombinant proteins and small molecule inhibitors to further elucidate the downstream signaling pathway activated by the “cytokine storm.”
