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Biliverdin, a natural product of heme catabolism, induces tolerance to cardiac allografts
Abstract
Biliverdin, a product of heme oxygenase-1 (HO-1) enzymatic action, is converted into bilirubin, which has been considered a waste product in the past. We now show that administration of biliverdin has a salutary effect in organ transplantation. A brief course of treatment with biliverdin leads to long-term survival of H-2 incompatible heart allografts. Furthermore, those recipients harboring long-surviving (>100 days) allografts were tolerant to donor antigens indicated by the acceptance of second donor strain hearts but not third-party grafts. Treatment with biliverdin decreased intragraft leukocyte infiltration and inhibited T cell proliferation. Likely related to tolerance induction, biliverdin interferes with T cell signaling by inhibiting activation of nuclear factor of activated T cells (NFAT) and nuclear factor kappaB (NF-kappaB), two transcription factors involved in interleukin-2 (IL-2) transcription and T cell proliferation, as well as suppressing Th1 interferon-gamma (IFN-gamma) production in vitro. These findings support the potential use of biliverdin, a natural product, in transplantation and other T cell mediated immune disorders.
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“whereas biliverdin induces tolerance to cardiac allografts by interfering with activation of nuclear factor of activated T cells (NFAT) and nuclear factor-κB (NF-κB), two transcription factors involved in interleukin-2 (IL-2) transcription and T cell activation and expansion (Yamashita et al., 2004).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Yamashita et al., 2004
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Metadata
- Authors
- Yamashita, K., McDaid, J., Öllinger, R., Tsui, T., Berberat, P. O., Usheva, A., Csizmadia, E., Smith, R. N., Soares, M. P., & Bach, F. H.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Queen Mary Hospital (CN)
- Harvard University (US)
- Corresponding author
- Yamashita, Kenichiro
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2004-02-20
- Volume
- 18
- Issue
- 6
- Pages
- 765-767
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2002874458
- Cited by
- 180
- References
- 36
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 10 · 2014: 8 · 2013: 8 · 2012: 15
- FWCI
- 6.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Institutes of Health (HL58688, HL67040)
- Pfizer
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- biliverdin, heme oxygenase-1, heart transplantation, allograft tolerance, T cell proliferation, NFAT, NF-κB, interleukin-2 transcription, interferon-gamma, Th1 response, heme degradation
- MeSH terms
- Animals, Biliverdine, Cell Movement, DNA-Binding Proteins, Graft Survival, Heme, Interleukin-2, Isoantigens, Lymphocyte Activation, Nuclear Proteins, T-Lymphocytes, Transcription Factors, Heart Transplantation, NF-kappa B, Transplantation Tolerance, NFATC Transcription Factors, Mice
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