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Cell and tissue research2022; 391(3); 523-544; doi: 10.1007/s00441-022-03726-6

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.

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.
© 2022. The Author(s).
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Publication Date: 2022-12-22 PubMed ID: 36543895PubMed Central: PMC9974687DOI: 10.1007/s00441-022-03726-6Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research article explores the detrimental effects of certain inflammation markers on horse tendon cells and concludes that suppressing these markers is insufficient to mitigate their negative impact, suggesting that future treatments should focus on specific cellular pathways.

Research Objectives

  • The study aimed to better understand the inflammatory pathways involved in tendinopathy, a condition characterized by tenderness or pain in a tendon.
  • It focused on three inflammatory cytokines – interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNFα), and interferon gamma (IFN-γ) – which have been hypothesized to exacerbate tendinopathy.

Methods and Findings

  • To study the effects of these cytokines on equine tenocytes – the primary cells within tendons – researchers used a 3-D collagen gel culture technique, which mimics the in vivo environment more closely than traditional petri-dish based cultures.
  • It was found that these cytokines significantly altered gene expression related to tendons and matrix metalloproteinase. Additionally, they impaired the tenocytes’ ability to contract, which hampers the cells’ normal function.
  • Importantly, the study showed that IL-1β, TNF, and IFN-γ when used together had a far more detrimental impact than when used separately, indicating their synergistic negative effect on tenocytes.
  • The researchers also attempted to alleviate these adverse effects by using IL-1RA, a suppressor of IL-1β, and factors produced by bone marrow-derived mesenchymal stromal cells (BM-MSCs). However, they found that neither of these approaches could counter the negative impact.
  • Upon closer study of the signaling pathways activated by the cytokines, it was observed that NF-κB (a protein complex involved in cellular responses) but not JNK, P38 MAPK, or STAT 1 was translocated to the nucleus and able to bind to DNA in tenocytes. This suggests that the NF-κB signalling pathway may be driving the adverse effects of the inflammatory cytokines.

Implications and Recommendations

  • This study contributes to current knowledge on tendinopathy by revealing that traditional methods of suppressing inflammation may not be an effective strategy for treating the condition.
  • Instead, it suggests that a better approach might be to target specific cellular pathways, such as NF-κB, to mitigate the harmful effects of inflammatory cytokines.

Cite This Article

APA
Smith EJ, Beaumont RE, McClellan A, Sze C, Palomino Lago E, Hazelgrove L, Dudhia J, Smith RKW, Guest DJ. (2022). 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 Tissue Res, 391(3), 523-544. https://doi.org/10.1007/s00441-022-03726-6

Publication

Cell and tissue research
ISSN: 1432-0878
NlmUniqueID: 0417625
Country: Germany
Language: English
Volume: 391
Issue: 3
Pages: 523-544

Researcher Affiliations

Smith, Emily J
  • Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK. ejsmith@rvc.ac.uk.
Beaumont, Ross E
  • Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
McClellan, Alyce
  • Centre for Preventative Medicine, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK.
Sze, Cheryl
  • Centre for Preventative Medicine, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK.
Palomino Lago, Esther
  • Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
Hazelgrove, Liberty
  • Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
  • Kingston University, River House, 53-57 High Street, Kingston upon Thames, Surrey, KT1 1LQ, UK.
Dudhia, Jayesh
  • Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
Smith, Roger K W
  • Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
Guest, Deborah J
  • Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK. djguest@rvc.ac.uk.

MeSH Terms

  • Humans
  • Animals
  • Horses
  • Tumor Necrosis Factor-alpha / metabolism
  • Interleukin-1beta / metabolism
  • NF-kappa B / metabolism
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Interferon-gamma / metabolism
  • Tenocytes / metabolism
  • Mesenchymal Stem Cells
  • Tendinopathy / metabolism
  • Cells, Cultured

Grant Funding

  • VET/RS/257 / Horserace Betting Levy Board
  • VET/PRI/782 / Horserace Betting Levy Board
  • S20-921-960 / Petplan Charitable Trust
  • S19-747-786 / Petplan Charitable Trust

Conflict of Interest Statement

The authors declare no competing interests.

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