By Yujean Kim
A cytokine storm is the uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Normally cytokines are key chemical messengers that allow cell to cell communication within the immune system. They amplify the immune response allowing a faster response to pathogens. However an excessive amount of cytokines can lead to vascular leakage, coagulopathy, organ dysfunction, transaminitis, and death (Turnquist et al., 2020). The cytokine storms can be caused by infection from pathogens and diseases. Recently it has been found in both the COVID-19 infection and cancer cells. Scientists speculate that IL-6 play a key role in the signaling pathway of this uncontrolled systemic inflammatory response.
IL-6 was initially discovered by Weissenbach in 1980. It is a polypeptide consisting of 4 alpha helices and is produced by almost all stromal cells and immune system cells. IL-6 plays a central role in the cytokine storm by undergoing the signal transduction pathway. This is accomplished by IL-6 binding to an IL-6 receptor. This complex then binds to the transmembrane glycoprotein 130 to activate many pathways. These include the JAK-STAT, RAS-RAF, SRC-YAP-NOTCH and AKT-P13K pathway. This promotes complex biological functions such as proliferation, differentiation, oxidative stress, and immune regulation (Zhang et al., 2020).
Since the 1960s, it has been identified that cytokine storms are produced in the presence of cancer. For example, in lung cancer cells, IL-6 acts directly on lung epithelial cells via the NF-κB signaling pathway under conditions of inflammation and carcinogen exposure, such as tobacco smoking. Tobacco smoking increases the risk of mutation of the KRAS gene. This in turn increases the expression of IL-6 in the lung epithelial cells and drives the cytokine storm. As a result there will be lung cancer proliferation and increase in tumorigenesis (Turnquist et al., 2020).
Along with cancer cells, cytokine storms are also identified in patients with severe SARS-CoV2 infection. It has been speculated that the cytokine storms cause the patients with SARS-CoV2 infection to be accompanied by respiratory failure, ARDS, and adverse clinical outcomes. This is due to the signaling pathway of IL-6 as mentioned above. The activation of the JAK-STAT signaling pathway in cells that do not express mIL-6R, such as endothelial cells, severely worsen the cytokine storm through secretion of the vascular endothelial growth factor and reduction of E-cadherin expression. This leads to vascular permeability and leakage which can result in the hypotension and pulmonary dysfunction seen in ARDS (Enzo, 2020).
With the exponential increase in SARS-CoV2 cases, the virus has caused a global pandemic this year. With a desperate need for a cure for the virus, many clinical trials have been taking place. Through identifying that cytokine storms worsen the condition of SARS-CoV2 cases, many drugs have been made to inhibit the cytokine storm. Examples include the Tocilizumab and the BTK inhibitor. Tocilizumab suppresses the trans-signaling pathways by acting as a monoclonal antibody against IL-6R. Tocilizumab was observed to be most effective on patients with high C-reactive protein levels. Since the C-reactive protein is induced by IL-6, it is speculated that the drug successfully inhibits IL-6. BTK inhibitor on the other hand, have previously been used to treat specific B cell malignancies. BTK activation induces NF-kB signaling which results in cytokine and chemokine production, including IL-6. As a result, by using BTK inhibitors, we can inhibit cytokine and chemokine production and overall decrease the proliferation and survival of malignant B cells.
In conclusion, through understanding the mechanism of cytokine storms, scientists now have a slightly better idea on how to deal with the current pandemic. This has also provided us with a further step in creating a drug to cure both cancer and COVID-19 patients. Perhaps this can revolutionise the therapeutic approaches of both cancer and SARS-CoV2: two infamously known diseases in human history.
Enzo Life Sciences. (2020) COVID-19 and the Cytokine Storm: The Crucial Role of IL-6. Enzo Life Sciences. Available from: https://www.enzolifesciences.com/science-center/technotes/2020/april/covid-19-and-the-cytokine-storm-the-crucial-role-of-il-6/ [Accessed: 15 October 2020].
Turnquist, C., Ryan, B. M., Horikawa, I., Harris, B. T. & Harris, C. C. (2020) Cytokine Storms in Cancer and COVID-19. Cancer Cell. 38(5), 598-601. Available from: doi: 10.1016/j.ccell.2020.09.019.
Zhang, C., Wu, Z., Li, J.-W., Zhao, H. & Wang, G.-Q. (2020) Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality, International Journal of Antimicrobial Agents. 55(5). Available from: doi: 10.1016/j.ijantimicag.2020.105954.