What is the role of Interleukin-6 (IL-6) in a cytokine storm?

From the Guidelines

Interleukin-6 (IL-6) plays a central role in cytokine storm, a life-threatening immune dysregulation characterized by excessive cytokine production. During cytokine storm, IL-6 is overproduced by activated immune cells and acts through both classical signaling (via membrane-bound IL-6 receptors) and trans-signaling (via soluble IL-6 receptors) pathways. This leads to widespread inflammation, vascular permeability, and multi-organ dysfunction. IL-6 promotes fever, acute phase protein production by the liver, and activates numerous immune cells including T cells, B cells, and macrophages, creating a dangerous positive feedback loop of inflammation. IL-6 also contributes to endothelial damage, coagulation abnormalities, and metabolic dysregulation during cytokine storm. Some key points to consider in the management of cytokine storm include:

• The use of IL-6 pathway inhibitors like tocilizumab (8 mg/kg IV, typically as a single dose) and sarilumab (400 mg IV once) to manage cytokine storm in conditions like COVID-19, CAR-T cell therapy complications, and certain autoimmune diseases 1.
• The importance of early intervention with these agents for optimal outcomes, as well as monitoring for potential adverse effects including increased infection risk, liver enzyme elevations, and neutropenia 1.
• The role of corticosteroids in the management of cytokine storm, particularly in cases where anti-IL-6 therapy is not effective or feasible 1.
• The need for supportive care, including management of organ toxicities, supplemental oxygen, and hemodynamic monitoring in severe cases of cytokine storm 1.

Therapeutically, IL-6 pathway inhibitors like tocilizumab are often used to manage cytokine storm, and have been shown to reduce the requirement of mechanical ventilation and the risk of ICU admission in patients with severe COVID-19 1. However, the current evidence is insufficient to support the use of tocilizumab outside clinical trials, and patients should be monitored for potential adverse effects including increased infection risk, liver enzyme elevations, and neutropenia 1. In addition, the use of anakinra, a recombinant human interleukin-1 receptor antagonist, has been proposed as a potential treatment for cytokine storm, particularly in cases where IL-6 inhibitors are not effective or feasible 1.

Overall, the management of cytokine storm requires a comprehensive approach that takes into account the underlying cause of the storm, the severity of the symptoms, and the potential risks and benefits of different treatment options. By prioritizing the use of IL-6 pathway inhibitors and supportive care, and carefully monitoring for potential adverse effects, clinicians can help to improve outcomes for patients with cytokine storm. It is also important to consider the role of other immunomodulatory agents, such as corticosteroids and anakinra, in the management of cytokine storm, and to continue to monitor the literature for updates on the best approaches to managing this complex and potentially life-threatening condition 1.

From the Research

Role of Interleukin-6 (IL-6) in a Cytokine Storm

• IL-6 is a pro-inflammatory cytokine that plays a significant role in the development of a cytokine storm, as it is elevated in various cytokine storm syndromes, including hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), and cytokine release syndrome (CRS) 2, 3.
• The interaction of IL-6 with its receptor complex can occur in several forms, making it clinically challenging to block its effects effectively 2.
• IL-6 contributes to host defense against infections and tissue injuries, but excessive synthesis can lead to an acute severe systemic inflammatory response, known as a cytokine storm 3.
• IL-6 signaling is mediated by building a complex of IL-6, the transmembrane IL-6 receptor (mIL-6R), or with soluble forms of IL-6R (sIL-6R), and the signal-transducing subunit molecule gp130, leading to pleiotropic functions of IL-6 4.

Mechanisms and Therapeutic Strategies

• The control of IL-6 signaling is regulated through the induction of suppressor molecules after activation of the IL-6 pathways, as well as through the presence of sIL-6R and gp130 forms in the blood 4.
• Overproduction of IL-6 and dysregulation of the IL-6 signaling pathways can result in inflammatory and autoimmune disorders, as well as cancer development, suggesting that IL-6 plays a significant role in the human cytokine network 4.
• Therapeutic agents, such as tocilizumab (anti-IL-6R humanized antibody) and siltuximab (an IL-6 antagonist), have been developed to inhibit IL-6 signaling and have been approved for the treatment of various diseases, including rheumatoid arthritis, cytokine release syndrome, and idiopathic multicentric Castleman's disease (iMCD) 2, 4, 5.
• Targeted treatment of cytokine storms, including the use of IL-6 blockade therapy, can effectively alleviate tissue damage while promoting the clearance of invading pathogens 6, 5.