Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Oct 26;21(21):7937.
doi: 10.3390/ijms21217937.

Interleukin-6: Molecule in the Intersection of Cancer, Ageing and COVID-19

Jan Brábek  1   2   3 , Milan Jakubek  3   4   5   6 , Fréderic Vellieux  3   5 , Jiří Novotný  3   7 , Michal Kolář  3   7 , Lukáš Lacina  3   5   8   9 , Pavol Szabo  8 , Karolína Strnadová  3   5   8 , Daniel Rösel  1   2   3 , Barbora Dvořánková  3   5   8 , Karel Smetana Jr  3   5   8
Affiliations
Review

Interleukin-6: Molecule in the Intersection of Cancer, Ageing and COVID-19

Jan Brábek et al. Int J Mol Sci. .

Abstract

Interleukin-6 (IL-6) is a cytokine with multifaceted effects playing a remarkable role in the initiation of the immune response. The increased level of this cytokine in the elderly seems to be associated with the chronic inflammatory setting of the microenvironment in aged individuals. IL-6 also represents one of the main signals in communication between cancer cells and their non-malignant neighbours within the tumour niche. IL-6 also participates in the development of a premetastatic niche and in the adjustment of the metabolism in terminal-stage patients suffering from a malignant disease. IL-6 is a fundamental factor of the cytokine storm in patients with severe COVID-19, where it is responsible for the fatal outcome of the disease. A better understanding of the role of IL-6 under physiological as well as pathological conditions and the preparation of new strategies for the therapeutic control of the IL-6 axis may help to manage the problems associated with the elderly, cancer, and serious viral infections.

Keywords: COVID-19; IL-6; ageing; cancer ecosystem; cancer-associated fibroblasts; cytokine; cytokine storm; tumour microenvironment.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Multiple genes of the interleukin-6 (IL-6) signalling pathway display gradual changes in transcription activity, differing among facial dermal fibroblasts from children (DF_FC), healthy adults (DF_FA), photodamaged dermal fibroblasts (DF) of patients suffering from basal cell carcinoma, and cancer-associated fibroblasts (CAFs) from basal cell carcinomas (BCCF) and cutaneous squamous cell carcinomas (SCCF).
Figure 2
Figure 2
Positive immunohistochemical detection of IL-6 in human cutaneous malignant melanoma. Nests of melanoma cells are highly positive for IL-6 (in brown). Stromal cells, including representatives of CAFs (arrows), are also somewhat positive in this staining. The bar is 100 μm.
Figure 3
Figure 3
Cultured cancer-associated fibroblasts from basal cell carcinoma and normal skin. Part of fibroblasts isolated from the tumour exhibit α-smooth muscle actin (SMA; green signal). All cells produce fibronectin (red signal). Nuclei were counterstained with 4’,6-diamidino-2-phenylindole (DAPI; blue signal) (A). Cultured normal dermal fibroblasts (DF) from the face of an aged donor (B) and CAFs from basal cell carcinoma (BCCF) from the face of the same donor (C) contain a very high proportion of senescent fibroblasts positive for senescence-associated acid β-galactosidase. The bar is 100 μm. While the senescent phenotype is present in both fibroblast groups, the cells differ in gene expression of several senescence-associated secretory phenotype (SASP) markers (D). The same genes are strongly expressed in CAFs from cutaneous squamous cell carcinoma (SCCF).
Figure 4
Figure 4
Migration of G361 melanoma cells from spheroids. G361 melanoma cells migrate from the heterogeneous spheres constructed from G361 melanoma cells and juvenile fibroblasts in 3D collagen gels without (A) and after tocilizumab application (B). Migration of melanoma cells was strongly reduced by the therapeutic humanised monoclonal antibody. Bar is 1 mm.
Figure 5
Figure 5
Structure of synthetic oestrogen analogues bazedoxifene and raloxifene.
Figure 6
Figure 6
Madindoline regioisomers (A) and (B).
Figure 7
Figure 7
MDL-101 derivative of madindoline.
Figure 8
Figure 8
20S,21-Epoxy-resibufogenin-3-formate (ERBF) inhibitor.
Figure 9
Figure 9
LMT-28 inhibitor.
Figure 10
Figure 10
Inhibitor TBMS47 (A—structure, B—model). Chemical structure of experimental substance TBMS47 (arrow) was designed to interact with IL-6R and its docking to the binding site of IL-6R recognizing IL-6. (C) TBMS47 inhibits in vitro proliferation of PaTu cells from pancreatic adenocarcinoma (represented here as Confluence %) in a concentration-dependent manner measured using Incucyte instrumentation (each line represents six technical replicates; error bars represent standard deviation of six wells).
See this image and copyright information in PMC

References

    1. Tissue Expression of IL6—Summary—The Human Protein Atlas. [(accessed on 21 September 2020)]; Available online: https://www.proteinatlas.org/ENSG00000136244-IL6/tissue.
    1. Zilberstein A., Ruggieri R., Korn J.H., Revel M. Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines. EMBO J. 1986;5:2529–2537. doi: 10.1002/j.1460-2075.1986.tb04531.x. - DOI - PMC - PubMed
    1. Haegeman G., Content J., Volckaert G., Derynck R., Tavernier J., Fiers W. Structural analysis of the sequence coding for an inducible 26-kDa protein in human fibroblasts. Eur. J. Biochem. 1986;159:625–632. doi: 10.1111/j.1432-1033.1986.tb09931.x. - DOI - PubMed
    1. Hirano T., Taga T., Nakano N., Yasukawa K., Kashiwamura S., Shimizu K., Nakajima K., Pyun K.H., Kishimoto T. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2) Proc. Natl. Acad. Sci. USA. 1985;82:5490–5494. doi: 10.1073/pnas.82.16.5490. - DOI - PMC - PubMed
    1. Brakenhoff J.P., de Groot E.R., Evers R.F., Pannekoek H., Aarden L.A. Molecular cloning and expression of hybridoma growth factor in Escherichia coli. J. Immunol. 1987;139:4116–4121. - PubMed

LinkOut - more resources