Leveraging genetic data to investigate the effects of interleukin-6 receptor signalling on levels of 40 circulating cytokines

Rezbieara Rahman
St George's University of London

Introduction/Background & aims Aim - To investigate the effects of interleukin-6 receptor (IL-6R) signalling on 40 circulating cytokines.

Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in inflammation and immunity^[1]. IL-6 exerts its effects via the interleukin-6 receptor (IL-6R), a type I cytokine receptor present in either the cell membrane (mIL-6R) or in soluble form (sIL-6R). There is growing interest in the role of IL-6 signalling in various diseases, including rheumatoid arthritis, cardiovascular disease and more recently coronavirus disease-2019 (COVID-19).

Drugs that inhibit IL-6R, such as tocilizumab, have already been licensed for use as a targeted therapy in rheumatoid arthritis and the cytokine storm associated with chimeric antigen receptor T-cell (CART) therapy^[2]. More recently, observational studies have shown that severity of COVID-19 disease and mortality correlate well with circulating IL-6 levels^[3]. As a result, there is an urgent need to dissect and better understand the consequences of IL-6R signalling pathways.

Method/Summary of work Variants within the IL-6R gene that proxy IL-6 signalling were selected. A two-sample Mendelian randomisation study was then conducted to explore the association of these variants with levels of 40 circulating cytokines using summary-level data from genome-wide association studies. Statistical sensitivity analyses were performed to investigate for potential genetic confounding, due to the association of genetic proxies for IL-6R signalling with circulating cytokines through pathways unrelated to IL-6R.

Results/Discussion There was evidence of a statistically significant association of genetically proxied IL-6R signalling with 10 circulating interleukins, chemokines, and growth factors (all p < 0.00125). IL-6R signalling was associated with reduced levels of inflammatory cytokines (interferon-ɣ, Interleukin-4, Interleukin-10, and Interleukin-12), chemokines (cutaneous T-cell-attracting chemokine, eotaxin and stromal cell-derived factor-1 α) and growth factors (fibroblast growth factor, granulocyte-colony stimulating factor and platelet-derived growth factor. There was no evidence of genetic confounding underlying these associations.

Conclusion(s) The findings from this study support feedback effects of IL-6R signalling on reducing levels of a range of circulating cytokines and thus identify pleiotropic inflammatory pathways that may be mediating some of its effects. These results provide novel insight into the mechanisms by which IL-6R signalling may be contributing to inflammatory and autoimmune disease, which can then be used to inform future research and clinical study.

Reference(s)

1. Tanaka T, Narazaki M, Kishimoto T. Il-6 in inflammation, Immunity, And disease. Cold Spring Harb Perspect Biol. 2014;6(10):16295-16296. doi:10.1101/cshperspect.a016295

2. Si S, Teachey DT. Spotlight on tocilizumab in the treatment of car-t-cell-induced cytokine release syndrome: Clinical evidence to date. Ther Clin Risk Manag. 2020;16:705-714. doi:10.2147/TCRM.S223468

3. Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: A meta-analysis. J Med Virol. 2020;92(11):2283-2285. doi:10.1002/jmv.25948