Heme oxygenase-1 protects pancreatic beta cells from apoptosis caused by various stimuli.
BACKGROUND
Several problems can occur after allogeneic islet transplantation: primary nonfunction, rejection, and the recurrence of autoimmune disease, which involve attack by the recipient's cytokines, T cells, natural killer cells, and monocytes on the donor's beta cells, which leads to beta-cell destruction. Recent studies have revealed that loss of transplanted islets is caused mainly by apoptosis. Heme oxygenase-1 (HO-1) is one of the antiapoptotic genes up-regulated under stress conditions. The aim of this work was to investigate any mechanisms of HO-1-mediated protection of beta cells from apoptosis.


METHODS
Apoptosis was assessed by comparison of viable transfected cells with and without apoptotic stimuli, and with and without HO-1 overexpression. Activation and function of p38 mitogen-activated protein kinase were determined using the specific inhibitor SB203580.


RESULTS
We have shown that HO-1 mediates antiapoptotic effects in beta cells. The percentage of apoptotic cells after stimulation with tumor necrosis factor a decreased from 75% without HO-1 to 5% when HO-1 was overexpressed. Our data indicate that HO-1 acts as a signal terminator of tumor necrosis factor alpha-induced apoptosis by modulation of the p38 mitogen-activated protein kinase pathway.


CONCLUSIONS
Profound cell stress that occurs in islets after transplantation, as well as at the onset of diabetes, results in beta-cell loss through apoptosis. Protection of beta cells by HO-1 improves their survival in vitro after various proapoptotic stimuli, suggesting that HO-1 suppresses one or several signaling pathways leading to apoptosis. We hypothesize that our in vitro findings can be extrapolated to the in vivo situation, and we propose that expression of HO-1 in islets may illuminate a valuable new approach to improving diabetes treatment.
Tobiasch
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E
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass. 02115, USA.
Günther
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L
Bach
F H
FH
D000818:Animals; D017209:Apoptosis; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000502:physiology*; D051547:Heme Oxygenase-1; D007515:Islets of Langerhans / Q000473:pathology*; D008565:Membrane Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases