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Nuclear factor kappaB protects pancreatic beta-cells from tumor necrosis factor-alpha-mediated apoptosis
Inik Chang1, Sunshin Kim, Ja Young Kim
1Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Kangnam-ku, Seoul 135-710, Korea.
Abstract:
Recent studies incriminating tumor necrosis factor (TNF)-alpha as the final effector in pancreatic beta-cell death in type 1 diabetes underscore the potential role of TNF-alpha-dependent NF-kappaB activation as an important modulator of pancreatic beta-cell death in autoimmune diabetes. Although nuclear factor (NF)-kappaB activation has been implicated in the protection of target cells against apoptosis by a variety of death effectors, its role in pancreatic islet cell death is not clear. We studied the role of NF-kappaB activation in pancreatic islet cell death by using a gamma-interferon (IFN-gamma)/TNF-alpha synergism model we had previously reported. TNF-alpha induced inhibitor of kappaB (IkappaB) degradation and p65 translocation from cytoplasm to nuclei in MIN6N8 insulinoma cells. The NF-kappaB DNA-binding nuclear complex activated by TNF-alpha contained both the p65 and p50 subunit. IFN-gamma pretreatment did not affect TNF-alpha-induced NF-kappaB activation. Treatment with a proteasome inhibitor blocked p65 translocation and induced susceptibility to TNF-alpha in otherwise resistant insulinoma cells or primary pancreatic islet cells. Specific inhibition of NF-kappaB activation by adenoviral transduction of IkappaB "superrepressor" also sensitized insulinoma cells and primary islet beta-cells to TNF-alpha-induced apoptosis. These results suggest the protective role of NF-kappaB activation against cytokine-mediated pancreatic beta-cell death, contrary to previous reports implicating NF-kappaB as a mediator of pancreatic islet cell death.
Insights
Nuclear factor-kappaB (NF-κB) activation protects pancreatic beta cells from death in autoimmune diabetes. Inhibiting NF-κB increases susceptibility to tumor necrosis factor-alpha (TNF-α)-induced apoptosis, contrary to prior research.
Area of Science:
- Immunology
- Endocrinology
- Cell Biology
Background:
- Tumor necrosis factor-alpha (TNF-α) is implicated in pancreatic beta-cell death in type 1 diabetes.
- The role of nuclear factor-kappaB (NF-κB) activation in pancreatic islet cell death is unclear, with conflicting evidence regarding its protective or detrimental effects.
Purpose of the Study:
- To investigate the role of NF-κB activation in cytokine-mediated pancreatic islet cell death.
- To clarify whether NF-κB activation protects or mediates pancreatic beta-cell death in autoimmune diabetes models.
Main Methods:
- Utilized a gamma-interferon (IFN-γ)/TNF-α synergism model in MIN6N8 insulinoma cells and primary pancreatic islet cells.
- Assessed NF-κB activation via inhibitor of kappaB (IκB) degradation and p65 translocation.
- Employed proteasome inhibitors and adenoviral transduction of IκB 'superrepressor' to modulate NF-κB activity.
Main Results:
- TNF-α induced NF-κB activation, characterized by IκB degradation and p65 translocation to the nucleus.
- IFN-γ pretreatment did not alter TNF-α-induced NF-κB activation.
- Proteasome inhibition or specific NF-κB inhibition sensitized insulinoma and primary islet beta-cells to TNF-α-induced apoptosis, indicating a protective role for NF-κB.
Conclusions:
- NF-κB activation plays a protective role against cytokine-mediated pancreatic beta-cell death.
- These findings suggest NF-κB activation is a protective mechanism, contradicting previous studies that implicated it as a mediator of pancreatic islet cell death.