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. 2021 May 18;2(5):100269.
doi: 10.1016/j.xcrm.2021.100269. Epub 2021 Apr 19.

Soluble interleukin-6 receptor in the COVID-19 cytokine storm syndrome

Luke Y C Chen  1   2 , Catherine M Biggs  3 , Shahin Jamal  4 , Sophie Stukas  5   6 , Cheryl L Wellington  5   6 , Mypinder S Sekhon  7
Affiliations

Soluble interleukin-6 receptor in the COVID-19 cytokine storm syndrome

Luke Y C Chen et al. Cell Rep Med. .

Abstract

Data suggest that interleukin (IL)-6 blockade could reduce mortality in severe COVID-19, yet IL-6 is only modestly elevated in most patients. Chen et al. describe the role of soluble interleukin-6 receptor (sIL-6R) in IL-6 trans-signaling and how understanding the IL-6:sIL-6R axis might help define and treat COVID-19 cytokine storm syndrome.

Keywords: COVID-19; cytokine storm; interleukin-6; interleukin-6 receptor; threshold concept; tocilizumab.

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Figures

Figure 1
Figure 1
IL-6 classic and trans-signaling and blockade Classic signaling via membrane-bound IL-6 receptor is restricted to immune cells (macrophages, lymphocytes, dendritic cells), hepatocytes, and gut epithelium. Other organs, such as lungs, myocardium, and nervous system, require soluble IL-6 receptor to initiate trans-signaling. The trans-signaling system is buffered by soluble glycoprotein 130, which binds and inhibits the IL-6:sIL-6R complex with picomolar affinity. Conventional dendritic cells overcome this buffering system by secreting sIL-6R directly as well as facilitating cleavage of mIL-6R to produce sIL-6R via the membrane-bound sheddase ADAM17. Siltuximab (antibody against IL-6), sarilumab, and tocilizumab (antibodies against IL-6:IL-6R) block both classic and trans-signaling. Olamkicept (sgp130Fc) specifically blocks trans-signaling. The intracellular TYK2/JAK1/JAK2/JAK3 system leads to upregulation of IL-6 target genes and is inhibited by Jak inhibitors such as baricitinib, ruxolitinib, and tofacitinib. The inhibition of TYK-2 (∗) is relatively weak relative to JAK inhibition by these molecules.
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