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IL-6 knockdown in a model of the human bone marrow, abrogates DNA damage induction in bystander cells post-chemotherapy induced cytokine release syndrome

Asurappulige, Harshini S. H.; Ladomery, Michael R.; Morse, H. Ruth

IL-6 knockdown in a model of the human bone marrow, abrogates DNA damage induction in bystander cells post-chemotherapy induced cytokine release syndrome Thumbnail


Authors

Harshini S. H. Asurappulige

Dr Ruth Morse Ruth.Morse@uwe.ac.uk
Associate Professor in Biomedical Sciences



Abstract

Following infection or exposure to therapeutic agents, an aggressive immune response may result, termed cytokine storm (CS) or cytokine release syndrome. Here the innate immune system becomes uncontrolled, leading to serious consequences including possible death. Patients surviving CS are at greater risk for de novo tumorigenesis, but it is unclear if any specific cytokines are directly responsible for this outcome. De novo tumorigenesis has been observed in donated cells exposed to CS following haematopoietic stem cell transplant (HSCT).

Modelling HSCT, we firstly demonstrated the release of CS levels from the HS-5 human bone marrow stromal cell line, post-exposure to chemotherapy. We then exposed the TK6 lymphoblast cell line to healthy and storm doses of IL-6 and measured increased genotoxicity via the micronucleus assay. During HSCT, haematopoietic cells are exposed to a complex mix of cytokines, so to determine if IL-6 was integral in a chemotherapy-induced bystander effect, we attempted to inhibit IL-6 from HS-5 cells using resatorvid or siRNA, treated with chlorambucil or mitoxantrone, and then co-cultured with bystander TK6 cells. Whilst resatorvid did not reduce IL-6 and did not reduce micronuclei in the bystander TK6 cells, siRNA inhibition reduced IL-6 to healthy in vivo levels, and micronuclei aligned with untreated controls.

Our data suggests that exposure to high IL-6 (in the absence of inflammatory cells) has potential to induce genetic damage and may contribute to de novo tumorigenesis post-CS. We suggest that for individuals with a proinflammatory profile, anti-IL-6 therapy may be an appropriate intervention to prevent complications post-CS.

Citation

Asurappulige, H. S. H., Ladomery, M. R., & Morse, H. R. (2024). IL-6 knockdown in a model of the human bone marrow, abrogates DNA damage induction in bystander cells post-chemotherapy induced cytokine release syndrome. Translational Oncology, 46, Article 102030. https://doi.org/10.1016/j.tranon.2024.102030

Journal Article Type Article
Acceptance Date Jun 5, 2024
Online Publication Date Jun 12, 2024
Publication Date Aug 1, 2024
Deposit Date Jun 12, 2024
Publicly Available Date Jun 12, 2024
Journal Translational Oncology
Electronic ISSN 1936-5233
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 46
Article Number 102030
DOI https://doi.org/10.1016/j.tranon.2024.102030
Keywords Cytokine storm, Cytokine release syndrome, Genetic toxicology, Bone marrow, Bystander effect
Public URL https://uwe-repository.worktribe.com/output/12041457

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