Effects of cytokines on rat pancreatic islet cell monolayer cultures: distinction between functional and cytotoxic effects on islet beta-cells.
Polypeptide products of mononuclear cells of the immune system (cytokines) have been reported to be cytotoxic to the insulin-producing pancreatic islet beta-cells. The objective of this study was to distinguish between reversible effects of cytokines on insulin secretion and irreversible cytotoxic effects on the islet beta-cells. When tested as single agents or added together at very low concentrations, interleukin 1 (IL-1), tumor necrosis factor (TNF), and interferon gamma (IFN-gamma) inhibited insulin release from rat islet cell monolayer cultures during 4 day incubations; however, this secretory function improved after the cytokines were removed. In contrast, combinations of slightly higher concentrations of IL-1, TNF, and IFN-gamma produced irreversible inhibition of insulin release, as well as decreased cell insulin content and proportional increase in cell lysis, measured as release of 51Cr from labeled islet cell cultures. These findings suggest that cytokine products of T lymphocytes (IFN-gamma) and macrophage/monocytic cells (IL-1, TNF) infiltrating pancreatic islets in "autoimmune" diabetes may interact synergistically to produce functional inhibition or lethal cytocidal effects on islet beta-cells, possibly accounting for reversible and irreversible stages of insulin-dependent diabetes.
Rabinovitch
A
A
Department of Medicine, University of Miami School of Medicine, FL 33101.
Baquerizo
H
H
Pukel
C
C
Sumoski
W
W
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003864:Depression, Chemical; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology; D004357:Drug Synergism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D011994:Recombinant Proteins / Q000494:pharmacology; D012636:Secretory Rate / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007328:Insulin; D007370:Interferon Type I; D007375:Interleukin-1; D007376:Interleukin-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma