Inhibition of interleukin-1 receptor-associated kinase (IRAK)-4 provides partial rescue of interleukin-1 beta induced functional and gene expression changes in equine tenocytes.
Abstract: Interleukin 1 beta (IL-1β) is upregulated following a tendon injury and in vitro studies have shown that it leads to numerous negative effects on tendon cell function and gene expression. IL-1β activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and we hypothesised that inhibiting NF-κB activation would mediate the negative effects of IL-1β on equine tendon cells in 3-dimensional (3D) cultures. Results: Here, we tested three inhibitors of NF-κB signalling (Bortezomib, BAY11-7082 and Wedelolactone) along withTJ-M2010-5, an inhibitor of MyD88, which is a critical adaptor protein for mediating IL-1β signalling. None of these inhibitors were able to rescue gel contraction by equine tenocytes exposed to IL-1β in 3D culture. However, the daily application of the interleukin-1 receptor-associated kinase (IRAK)-4 inhibitor PF-06650833 resulted in a partial rescue of collagen contraction and interleukin-6 (IL-6) production by equine tenocytes in 3D culture. Global gene expression using RNA sequencing also revealed a partial rescue, although this was not as complete as that achieved using interleukin-1 receptor antagonist protein (IL1Ra), with many inflammatory pathways remaining upregulated. ENPP2 expression was significantly increased by IL-1β and rescued by both IL1Ra and PF-06650833 suggesting ENPP2 may be involved in collagen contraction. However, direct ENPP2 inhibition does not rescue IL-1β mediated inhibition of contraction and ENPP2 inhibition alone reduces collagen contraction. Conclusions: Together, this data demonstrates that IL-1β has a broad mechanism of action on tendon cells which cannot be fully mediated by targeting specific parts of the signalling pathway.
© 2025. The Author(s).
Publication Date: 2025-11-06 PubMed ID: 41196436PubMed Central: PMC12592280DOI: 10.1007/s11033-025-11219-2Google Scholar: Lookup
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Summary
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Overview
- This study investigates how inhibiting specific components of the interleukin-1 beta (IL-1β) signaling pathway affects the negative impacts of IL-1β on equine tendon cells, particularly focusing on cellular function and gene expression changes in three-dimensional (3D) cultures.
- The research found that blocking interleukin-1 receptor-associated kinase 4 (IRAK-4) partially alleviates IL-1β-induced dysfunction and gene expression changes in these tendon cells, though not completely.
Background
- IL-1β is a pro-inflammatory cytokine upregulated after tendon injury and is known to disrupt normal tendon cell function and gene expression.
- IL-1β signals through pathways involving nuclear factor kappa B (NF-κB), leading to inflammation and reduced tendon healing capacity.
- The MyD88 adaptor protein and IRAK-4 kinase are key components in transmitting IL-1β signals inside cells.
- Strategies targeting these signaling molecules may help in counteracting IL-1β-induced damage in tendon cells.
Study Objectives
- To test whether inhibition of NF-κB activation or upstream signaling components could reverse IL-1β’s negative effects on equine tenocytes (tendon cells) in a 3D culture model.
- To evaluate the effects of different pharmacological inhibitors on cell function (gel contraction) and gene expression changes induced by IL-1β.
Methods
- Equine tenocytes were cultured in 3D collagen gels treated with IL-1β to mimic post-injury inflammatory conditions.
- Multiple inhibitors were tested:
- Bortezomib, BAY11-7082, and Wedelolactone: inhibitors acting downstream on NF-κB signaling.
- TJ-M2010-5: an inhibitor of MyD88, an adaptor protein directly involved in IL-1β signaling.
- PF-06650833: a specific inhibitor of IRAK-4 kinase.
- Interleukin-1 receptor antagonist protein (IL1Ra) was used as a reference control to block IL-1β receptor activation.
- Cell function was measured through contraction of the collagen gels, a process related to tendon healing.
- IL-6 production, a marker of inflammation, was also assessed.
- Gene expression changes were analyzed using RNA sequencing (RNA-seq) to understand global effects of IL-1β and the inhibitors.
- Expression and role of the gene ENPP2 were specifically studied, given its regulation by IL-1β and potential involvement in cell contraction.
Key Findings
- None of the NF-κB inhibitors (Bortezomib, BAY11-7082, Wedelolactone) nor the MyD88 inhibitor (TJ-M2010-5) were able to restore normal collagen gel contraction in the presence of IL-1β.
- The IRAK-4 inhibitor PF-06650833 partially rescued the ability of tenocytes to contract collagen gels and partially reduced IL-6 production.
- RNA sequencing showed that PF-06650833 partially reversed IL-1β-induced gene expression changes, but this rescue was incomplete compared to IL1Ra which had a broader inhibitory effect on inflammatory pathways.
- The gene ENPP2 was strongly upregulated by IL-1β and this increase was reversed by both IL1Ra and PF-06650833.
- However, direct inhibition of ENPP2 did not reverse the IL-1β-induced reduction in collagen contraction and instead reduced contraction when inhibited alone, indicating a complex role.
Interpretation and Conclusions
- IL-1β acts through multiple pathways to influence tendon cell function and gene expression, making it challenging to fully mitigate its effects by targeting individual signaling components.
- IRAK-4 inhibition can partially protect tendon cells from IL-1β effects but does not restore full function, suggesting redundancy or parallel pathways contribute to IL-1β’s impact.
- The partial rescue by PF-06650833 implies that IRAK-4 is an important but not exclusive mediator of IL-1β signaling in tendon cells.
- The incomplete gene expression rescue and persistent inflammation after IRAK-4 inhibition highlight the complexity of IL-1β signaling and its regulation of tendon cell biology.
- ENPP2’s role in tenocyte contraction and its regulation by IL-1β suggest it may be a downstream effector or marker but not a straightforward therapeutic target because its inhibition also reduces contraction.
- These findings underline the need for broader or multi-target therapeutic strategies to effectively counteract IL-1β-induced tendon damage and improve healing outcomes.
Cite This Article
APA
Beaumont RE, Flood C, Guest DJ.
(2025).
Inhibition of interleukin-1 receptor-associated kinase (IRAK)-4 provides partial rescue of interleukin-1 beta induced functional and gene expression changes in equine tenocytes.
Mol Biol Rep, 53(1), 54.
https://doi.org/10.1007/s11033-025-11219-2 Publication
Researcher Affiliations
- Centre for Vaccinology and Regenerative Medicine, Clinical Science and Services, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
- Centre for Vaccinology and Regenerative Medicine, Clinical Science and Services, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
- Centre for Vaccinology and Regenerative Medicine, Clinical Science and Services, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK. djguest@rvc.ac.uk.
MeSH Terms
- Animals
- Horses
- Interleukin-1beta / metabolism
- Interleukin-1beta / pharmacology
- Tenocytes / metabolism
- Tenocytes / drug effects
- Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors
- Interleukin-1 Receptor-Associated Kinases / metabolism
- Interleukin-1 Receptor-Associated Kinases / genetics
- Signal Transduction / drug effects
- NF-kappa B / metabolism
- Sulfones / pharmacology
- Tendons / metabolism
- Tendons / cytology
- Nitriles / pharmacology
- Gene Expression Regulation / drug effects
- Cells, Cultured
Grant Funding
- S22-1151-1190 / Petplan Charitable Trust
- S22-1151-1190 / Petplan Charitable Trust
Conflict of Interest Statement
Declarations. Competing interests: The authors declare no competing interests. Ethics approval: The cells used in this study were collected and used with the approval of the Royal Veterinary College Clinical Research Ethical Review Board (URN 2020 2017-2).
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