The role of Interleukin 1 receptor antagonist in mesenchymal stem cell‐based tissue repair and regeneration
Abstract
Interleukin (IL)‐1 receptor antagonist (IL‐1Ra), a naturally occurring antagonist of IL‐1α/IL‐1β signaling pathways, has been attributed to the immunosuppressive effects of mesenchymal stem cells (MSCs). MSCs, in IL‐1Ra‐dependent manner, suppressed production of IL‐1β in dermal macrophages, induced their polarization in anti‐inflammatory M2 phenotype, attenuated antigen‐presenting properties of dendritic cells (DCs), and promoted expansion of immunosuppressive T regulatory cells in the skin, which resulted in enhanced repair of the nonhealing wounds. Reduced activation of inflammasome and suppressed production of IL‐1β in macrophages were mainly responsible for beneficial effects of MSC‐derived IL‐1Ra in alleviation of acute lung injury, dry eye syndrome, and corneal injury. Through the production of IL‐1Ra, MSCs reduced migration of DCs to the draining lymph nodes and attenuated generation of inflammatory Th1 and Th17 cells that resulted in alleviation of fulminant hepatitis and rheumatoid arthritis. MSCs, in IL‐1Ra‐dependent manner, reduced liver fibrosis by suppressing production of Type I collagen in hepatic stellate cells. IL‐1Ra was, at least partially, responsible for enhanced proliferation of hepatocytes and chondrocytes in MSC‐treated animals with partial hepatectomy and osteoarthritis. Despite of these beneficial effects, IL‐1Ra‐dependent inhibition of IL‐1α/IL‐1β‐signaling significantly increased risk of infections. Therefore, future experimental and clinical studies should delineate potential side effects of MSC‐derived IL‐1Ra before IL‐1Ra‐overexpressing MSCs could be used as a potentially new therapeutic agent for the treatment of acute and chronic inflammatory diseases.
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IL-1RA-producing MSCs completely revert lung inflammation in mice by suppressing production of IL-1α, IL-1β and TNF-α by alveolar macrophages.
“In fact, IL-1RA-producing MSCs has completely reverted lung inflammation in mice by suppressing production of IL-1α, IL-1β and TNF-α by alveolar macrophages [74], [175].”
From Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? (2025) · cites this paper as [74]
There are several studies revealing beneficial effects of MSCs in lung fibrosis and acute lung injury.
“There are several studies revealing the beneficial effects of MSCs in lung fibrosis and acute lung injury [74], [171], [172], [173], [174], [175], [176], [177], [178] (Fig. 4).”
From Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? (2025) · cites this paper as [74]
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- Authors
- Harrell, C. R., Markovic, B. S., Fellabaum, C., Arsenijevic, N., Djonov, V., & Volarevic, V.
- Affiliations
- Regenerative Processing Plant, LLC Palm Harbor Florida
- Faculty of Medical Sciences, Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research University of Kragujevac Kragujevac Serbia
- University of Bern (CH)
- University of Kragujevac (RS)
- Corresponding author
- Volarevic, Vladislav
- Venue
- BioFactors
- Publisher
- Wiley
- Published
- 2019-11-22
- Volume
- 46
- Issue
- 2
- Pages
- 263-275
- ISSN
- 0951-6433 (ISSN-L)
- 1872-8081
- OpenAlex
- W2990592352
- Cited by
- 106
- References
- 86
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 30 · 2023: 15 · 2022: 21 · 2021: 19 · 2020: 4
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- BioFactors (publishedVersion)
- PubMed (publishedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- interleukin-1 receptor antagonist, mesenchymal stem cells, IL-1β signaling, immunosuppression, macrophage polarization, M2 macrophages, dendritic cells, regulatory T cells, chronic wounds, acute lung injury, dry eye, corneal injury, fulminant hepatitis, rheumatoid arthritis, liver fibrosis, hepatic stellate cells, osteoarthritis, partial hepatectomy, infection risk, tissue regeneration
- MeSH terms
- Humans, Regeneration, Cell Proliferation, Interleukin 1 Receptor Antagonist Protein, Mesenchymal Stem Cells
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