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*Pancreatic Cancer
Endocrinology Vol. 140, No. 7 3219-3227
Copyright © 1999 by The Endocrine Society

ARTICLES

Tumor Necrosis Factor-{alpha}-Activated Cell Death Pathways in NIT-1 Insulinoma Cells and Primary Pancreatic ß Cells1

Leigh A. Stephens2, Helen E. Thomas2, Li Ming, Matthias Grell RIMA DARWICHE, Leonid Volodin and Thomas W. H. Kay

The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Parkville, 3050, Victoria, Australia

Address all correspondence and requests for reprints to: Dr. T. W. H. Kay, Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Victoria, 3050, Australia. E-mail: kay{at}wehi.edu.au

Tumor necrosis factor-{alpha} (TNF{alpha}) is a potential mediator of ß cell destruction in insulin-dependent diabetes mellitus. We have studied TNF-responsive pathways leading to apoptosis in ß cells. Primary ß cells express low levels of the type I TNF receptor (TNFR1) but do not express the type 2 receptor (TNFR2). Evidence for TNFR1 expression on ß cells came from flow cytometry using monoclonal antibodies specific for TNFR1 and TNFR2 and from RT-PCR of ß cell RNA. NIT-1 insulinoma cells similarly expressed TNFR1 (at higher levels than primary ß cells) as detected by flow cytometry and radio-binding studies. TNF induced NF-{kappa}B activation in both primary islet cells and NIT-1 cells. Apoptosis in response to TNF{alpha} was observed in NIT-1 cells whereas apoptosis of primary ß cells required both TNF{alpha} and interferon-{gamma} (IFN{gamma}). Apoptosis could be prevented in NIT-1 cells by expression of dominant negative Fas-associating protein with death domain (dnFADD). Apoptosis in NIT-1 cells was increased by coincubation with IFN{gamma}, which also increased caspase 1 expression. These data show that TNF-activated pathways capable of inducing apoptotic cell death are present in ß cells. Caspase activation is the dominant pathway of TNF-induced cell death in NIT-1 cells and may be an important mechanism of ß cell damage in insulin-dependent diabetes mellitus.




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