Aims/hypothesis
In the human pancreas, a close topographic relationship exists between duct cells and beta cells. This explains the high proportion of duct cells in isolated human islet preparations. We investigated whether human duct cells are a source of TNF
-mediated interactions with beta cells and immune cells. This cytokine has been implicated in the development of autoimmune diabetes in mice.
Methods
Human duct cells were isolated from donor pancreases and examined for their ability to produce TNF
following a stress-signalling pathway. Duct-cell-released TNF
was tested for its in vitro effects on survival of human beta cells and on activation of human dendritic cells.
Results
Exposure of human pancreatic duct cells to interleukin-1
(IL-1
) induces TNF
gene expression, synthesis of the 26,000 M
r TNF
precursor and conversion to the 17,000 M
r mature form, which is rapidly released. This effect is NO-independent and involves p38 MAPK and NF-
B signalling. Duct-cell-released TNF
contributed to cytokine-induced apoptosis of isolated human beta cells. It also induced activation of human dendritic cells.
Conclusions/interpretation
Human pancreatic duct cells are a potential source of TNF
that can cause apoptosis of neighbouring beta cells and initiate an immune response through activation of dendritic cells. They may thus actively participate in inflammatory and immune processes that threaten beta cells during development of diabetes or after human islet cell grafts have been implanted.
Keywords Apoptosis - Diabetes mellitus - Insulin - Islets of Langerhans - Pancreas