Interferon-gamma sensitizes rat pancreatic islet cells to lysis by cytokines and cytotoxic cells.
Immunoregulatory polypeptides (cytokines) produced by mononuclear cells of the immune system can inhibit insulin secretion and may be cytotoxic to pancreatic islet beta cells. We used a modified 51Cr release cytotoxicity assay to define the interactive cytotoxic effects of interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon gamma (IFN-gamma) on rat islet cells in monolayer culture. We here demonstrate that (a) IFN-gamma, but not IL-1 or TNF, can sensitize islet cells to subsequent cytolysis by other cytokines (IL-1 or TNF); (b) the cytolytic effect of sequential addition of IFN-gamma, then IL-1 or TNF (approximately 35-40% 51Cr release) is similar to that produced by the concurrent addition of IFN-gamma plus IL-1 or TNF; (c) the priming effect of IFN-gamma persists for 3 to 6 or more days after its removal; and (d) islet cells preincubated with IFN-gamma are also more sensitive to cytolysis by splenic mononuclear cells from diabetes-prone BB/Wor rats. These findings suggest that IFN-gamma produced by activated T lymphocytes and monocytic cells infiltrating islets in Type 1 diabetes may play a direct and important role in sensitizing beta cells to damage by other cytokines (IL-1, TNF) and cytotoxic cells in the immune/inflammatory infiltrate.
Baquerizo
H
H
Department of Medicine, Muttart Diabetes Research and Training Centre, Edmonton, Alberta, Canada.
Rabinovitch
A
A
D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology*; D051381:Rats; D011913:Rats, Inbred BB; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*
D001685:Biological Factors; D016207:Cytokines; D007371:Interferon-gamma