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Biliverdin, a natural product of heme catabolism, induces tolerance to cardiac allografts
Author(s) -
Yamashita Kenichiro,
McDaid James,
Öllinger Robert,
Tsui TungYu,
Berberat Pascal O.,
Usheva Anny,
Csizmadia Eva,
Smith R. Neal,
Soares Miguel P.,
Bach Fritz H.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0839fje
Subject(s) - biliverdin , heme , catabolism , natural product , chemistry , heme oxygenase , biochemistry , metabolism , enzyme
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 κB (NF‐κB), two transcription factors involved in interleukin‐2 (IL‐2) transcription and T cell proliferation, as well as suppressing Th1 interferon‐γ (IFN‐γ) production in vitro. These findings support the potential use of biliverdin, a natural product, in transplantation and other T cell mediated immune disorders.