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Toll‐like receptor 4 suppression leads to islet allograft survival
Author(s) -
Goldberg Alyssa,
Parolini Margherita,
Chin Beek Y.,
Czismadia Eva,
Otterbein Leo E.,
Bach Fritz H.,
Wang Hongjun
Publication year - 2007
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.06-7910com
Subject(s) - islet , tlr4 , transplantation , inflammation , toll like receptor , receptor , immune tolerance , apoptosis , medicine , immune system , immunology , cancer research , biology , endocrinology , diabetes mellitus , innate immune system , biochemistry
Carbon monoxide (CO) exposure of an islet donor frequently leads to islet allograft long‐term survival and tolerance in recipients. We show here that CO confers its protective effects at least in part by suppressing Toll‐like receptor 4 (TLR4) up‐regulation in pancreatic β cells. TLR4 is normally up‐regulated in islets during the isolation procedure; donor treatment with CO suppresses TLR4 expression in isolated islets as well as in transplanted grafts. TLR4 up‐regulation allows initiation of inflammation, which leads to islet allograft rejection;islet grafts from TLR4‐deficient mice survive indefinitely in BALB/c recipients and show significantly less inflammation at various days after transplantation compared with grafts from a control donor. Isolated islets preinfected with a TLR4 dominant negative virus before transplantation demonstrated prolonged survival in recipients. Despite the salutary effects of TLR4 suppression, HO‐1 expression is still needed in the recipient for islet survival: TLR4‐deficient islets were rejected promptly after being transplanted into recipients in which HO‐1 activity was blocked. In addition, incubation of an insulinoma cell line, βTC3, with an anti‐TLR4 antibody protects those cells from cytokine‐induced apoptosis. Our data suggest that TLR4 induction in β cells is involved in β cell death and graft rejection after transplantation. CO exposure protects islets from rejection by blocking TLR4 up‐regulation.—Goldberg, A., Parolini, M., Chin, B. Y., Czismadia, E., Otterbein, L. E., Bach, F. H., Wang, H. Toll‐like receptor 4 suppression leads to islet allograft survival. FASEB J. 21, 2840–2848 (2007)