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Methods to Assess Beta Cell Death Mediated by Cytotoxic T Lymphocytes
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Methods to Assess Beta Cell Death Mediated by Cytotoxic T Lymphocytes

Published on: June 16, 2011

Tumor necrosis factor-alpha-activated cell death pathways in NIT-1 insulinoma cells and primary pancreatic beta cells

L A Stephens1, H E Thomas, L Ming

  • 1The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Parkville, Victoria, Australia.

Endocrinology
|June 29, 1999
PubMed

Insights

Tumor necrosis factor-alpha (TNFalpha) can trigger beta cell death pathways relevant to type 1 diabetes. While TNFalpha alone induces apoptosis in insulinoma cells, primary beta cells require interferon-gamma for this response.

Area of Science:

  • Immunology
  • Endocrinology
  • Cell Biology

Background:

  • Insulin-dependent diabetes mellitus (IDDM) involves beta cell destruction.
  • Tumor necrosis factor-alpha (TNFalpha) is implicated as a mediator in this process.
  • Understanding TNFalpha-induced apoptosis in beta cells is crucial for IDDM research.

Purpose of the Study:

  • To investigate TNFalpha-responsive pathways leading to apoptosis in beta cells.
  • To characterize TNF receptor expression and function in primary beta cells and insulinoma cells.
  • To elucidate the mechanisms of TNFalpha-induced beta cell death.

Main Methods:

  • Flow cytometry and RT-PCR to detect TNF receptor (TNFR1, TNFR2) expression on primary beta cells and NIT-1 insulinoma cells.
  • Assessment of NF-kappaB activation in response to TNFalpha.
  • Induction of apoptosis in beta cells using TNFalpha, interferon-gamma (IFNgamma), and dominant-negative FADD (dnFADD).
  • Caspase activity assays.

Main Results:

  • Primary beta cells express TNFR1 but not TNFR2; NIT-1 cells express TNFR1 at higher levels.
  • TNFalpha activates NF-kappaB in both cell types.
  • TNFalpha induces apoptosis in NIT-1 cells, which can be blocked by dnFADD.
  • Apoptosis of primary beta cells requires both TNFalpha and IFNgamma.
  • IFNgamma enhances TNFalpha-induced apoptosis in NIT-1 cells and increases caspase 1 expression.

Conclusions:

  • TNFalpha-activated apoptotic pathways exist in beta cells.
  • Caspase activation is a key mechanism in TNFalpha-induced NIT-1 cell death.
  • These pathways may contribute to beta cell damage in type 1 diabetes.

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