Human pancreatic duct cells can produce tumour necrosis factor-alpha that damages neighbouring beta cells and activates dendritic cells.
OBJECTIVE
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 TNFalpha-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 TNFalpha following a stress-signalling pathway. Duct-cell-released TNFalpha 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-1beta (IL-1beta) induces TNFalpha gene expression, synthesis of the 26,000 M(r) TNFalpha 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-kappaB signalling. Duct-cell-released TNFalpha contributed to cytokine-induced apoptosis of isolated human beta cells. It also induced activation of human dendritic cells.


CONCLUSIONS
Human pancreatic duct cells are a potential source of TNFalpha 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.
Movahedi
B
B
Diabetes Research Centre, Brussels Free University-VUB and JDRF Centre for Beta Cell Therapy in Europe, Laarbeeklaan 103, 1090 Brussels, Belgium.
Van de Casteele
M
M
Caluwé
N
N
Stangé
G
G
Breckpot
K
K
Thielemans
K
K
Vreugdenhil
G
G
Mathieu
C
C
Pipeleers
D
D
D017209:Apoptosis; D001530:Belgium; D020126:Brefeldin A / Q000494:pharmacology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007375:Interleukin-1 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007633:Keratins / Q000737:chemistry / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D010183:Pancreatic Ducts / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D011498:Protein Precursors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007375:Interleukin-1; D016328:NF-kappa B; D011498:Protein Precursors; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D020126:Brefeldin A; D007633:Keratins; D003513:Cycloheximide; D048051:p38 Mitogen-Activated Protein Kinases