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 β cells, which leads to β-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 β 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 β cells. The percentage of apoptotic cells after stimulation with tumor necrosis factor α 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 α-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 β-cell loss through apoptosis. Protection of β 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.
- diabetes mellitus
- heme oxygenase-1
- p38 mitogen-activated protein kinase
- beta cells
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