Tumour necrosis factor alpha, Interleukin 1 beta and Interferon gamma have detrimental effects on equine tenocytes that cannot be rescued by IL-1RA or mesenchymal stromal cell-derived factors

Guest, Deborah; Smith, Emily; Beaumont, Ross; McClellan, Alyce; Sze, Cheryl; Palomino Lago, Esther; Hazelgrove, Liberty; Dudhia, Jayesh; Smith, Roger

Abstract

Tendon injuries occur commonly in both human and equine athletes, and poor tendon regeneration leads to functionally
deficient scar tissue and an increased frequency of re-injury. Despite evidence suggesting inadequate resolution of inflammation
leads to fibrotic healing, our understanding of the inflammatory pathways implicated in tendinopathy remains
poorly understood, meaning successful targeted treatments are lacking. Here, we demonstrate IL-1β, TNFα and IFN-γ work
synergistically to induce greater detrimental consequences for equine tenocytes than when used individually. This includes
altering tendon associated and matrix metalloproteinase gene expression and impairing the cells’ ability to contract a 3-D
collagen gel, a culture technique which more closely resembles the in vivo environment. Moreover, these adverse effects
cannot be rescued by direct suppression of IL-1β using IL-1RA or factors produced by BM-MSCs. Furthermore, we provide
evidence that NF-κB, but not JNK, P38 MAPK or STAT 1, is translocated to the nucleus and able to bind to DNA in tenocytes
following TNFα and IL-1β stimulation, suggesting this signalling cascade may be responsible for the adverse downstream
consequences of these inflammatory cytokines. We suggest a superior approach for treatment of tendinopathy may therefore
be to target specific signalling pathways such as NF-κB.

Citation

Guest, D., Smith, E., Beaumont, R., McClellan, A., Sze, C., Palomino Lago, E., …Smith, R. (in press). Tumour necrosis factor alpha, Interleukin 1 beta and Interferon gamma have detrimental effects on equine tenocytes that cannot be rescued by IL-1RA or mesenchymal stromal cell-derived factors. Cell and Tissue Research, https://doi.org/10.1007/s00441-022-03726-6

• Journal Article Type: Article
• Acceptance Date: Dec 10, 2022
• Online Publication Date: Dec 22, 2022
• Deposit Date: Dec 15, 2022
• Publicly Available Date: Jan 9, 2023
• Print ISSN: 0302-766X
• Publisher: Springer
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1007/s00441-022-03726-6
• Publisher URL: https://link.springer.com/article/10.1007/s00441-022-03726-6