Interleukin-6 Perpetrator of the COVID-19 Cytokine Storm

Abstract

COVID-19 has emerged as a global pandemic. It is mainly manifested as pneumonia which may deteriorate into severe respiratory failure. The major hallmark of the disease is the systemic inflammatory immune response characterized by Cytokine Storm (CS). CS is marked by elevated levels of inflammatory cytokines, mainly interleukin-6 (IL-6), IL-8, IL-10, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Of these, IL-6 is found to be significantly associated with higher mortality. IL-6 is also a robust marker for predicting disease prognosis and deterioration of clinical profile. In this review, the pivotal role played by IL-6 in the immuno-pathology of COVID-19 has been illustrated. The role of IL-6 as a pleiotropic cytokine executing both pro and anti-inflammatory activities has been reviewed. ADAM 10, a metalloproteinase switches the anti-inflammatory pathway of IL-6 to pro inflammatory hence blocking the action of ADAM 10 could be a new therapeutic strategy to mitigate the proinflammatory action of IL-6. Furthermore, we explore the role of anti-IL6 agents, IL-6 receptor antibodies which were being used for autoimmune diseases but now are being repurposed for the therapy of COVID-19.

Predictors of poor outcome in tocilizumab treated patients with Sars-CoV-2 related severe respiratory failure: A multicentre real world study

“…Blocking the cytokine cascade at different points, the dysregulation of inflammatory, immune and coagulation systems could be avoided and pulmonary damage limited reducing the risk of respiratory failure progression. Therefore it’s not surprising that research has focused on molecules aimed to avoid or estinguish the SARS-CoV2 related cytokine storm, such as Interleukin-1 (Anakinra) or IL-6 (Tocilizumab, Sarilumab) antagonists or JAK-STAT inhibitors (Baricitinib, Ruxolitinib) [6] . The IL-6 inhibitor Tocilizumab is a humanized monoclonal antibody which binds both with membrane bound and soluble receptors for IL-6 so blocking the signal transduction by which the JAK-STAT is activated perpetrating the cytokine storm [7] .…”

Hypoxic and Hyperoxic Breathing as a Complement to Low-Intensity Physical Exercise Programs: A Proof-of-Principle Study

“…In the presence of unregulated inflammatory response, proinflammatory and anti-inflammatory pathways are leading to a complex pattern of systemic activations consequent to cytokine storm, resulting in immune system impairment and proinflammatory imbalance. Downstream, the resulting "massive" inflammatory cascade, is responsible for global autonomic, endocrine, hematological, and immunological alterations, leading to a reversible or irreversible end-organ dysfunction and even death, as we have dramatically seen in the course of the current pandemic of severe acute respiratory syndrome corona virus 2 (SARS CoV-2) [6,7].…”

Sarilumab Administration in COVID-19 Patients: Literature Review and Considerations

“…As regards signaling modalities, trans-signaling and trans-presentation are suggested to be the main pathogenic pathways in severe progressive COVID-19, accounting for disseminated inflammation up to shock, secondary to cytokine-mediated dysfunction [ 50 ], whereas IL-6 cis-signaling, exerting negative feedback mechanisms on pro-inflammatory cytokines, appears as predominant in the advanced stages of disease in which the IL-6 peak is accompanied by elevated IL-10 concentrations, endeavoring to restore homeostatic conditions [ 51 ].…”