Heme Oxygenase-1 Protects Pancreatic β Cells from Apoptosis Caused by Various Stimuli
- 1 November 2001
- journal article
- Published by SAGE Publications in Journal of Investigative Medicine
- Vol. 49 (6_suppl), 566-571
- https://doi.org/10.2310/6650.2001.33721
Abstract
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.Keywords
This publication has 43 references indexed in Scilit:
- Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive RegimenNew England Journal of Medicine, 2000
- Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcriptionOncogene, 2000
- Bcl-2 and Bcl-XL serve an anti-inflammatory function in endothelial cells through inhibition of NF-κBJCI Insight, 1999
- Induction of Apoptosis by SB202190 through Inhibition of p38β Mitogen-activated Protein KinasePublished by Elsevier BV ,1998
- Early Activation of c-Jun N-terminal Kinase and p38 Kinase Regulate Cell Survival in Response to Tumor Necrosis Factor αPublished by Elsevier BV ,1998
- Nitric Oxide Primes Pancreatic β Cells for Fas-mediated Destruction in Insulin-dependent Diabetes MellitusThe Journal of Experimental Medicine, 1997
- Kinetic Mechanism for p38 MAP KinaseBiochemistry, 1997
- THE HEME OXYGENASE SYSTEM:A Regulator of Second Messenger GasesAnnual Review of Pharmacology and Toxicology, 1997
- Cytokines activate the nuclear factor κB (NF‐κB) and induce nitric oxide production in human pancreatic isletsFEBS Letters, 1996
- Pancreatic beta cells in insulin‐dependent diabetesDiabetes/Metabolism Research and Reviews, 1992