Destruction of Rat Islet Cell Monolayers by Cytokines: Synergistic Interactions of Interferon-γ, Tumor Necrosis Factor, Lymphotoxin, and Interleukin 1

TLDR

An assay was developed to detect cytokine‑induced cytotoxicity in rat pancreatic islet cell monolayers, measuring cell lysis via a 51Cr‑release assay after 4 days of incubation with various cytokines. The study found that while interferon‑γ alone caused only modest, dose‑dependent islet cell lysis, combinations of TNF or lymphotoxin with IL‑1, TNF or lymphotoxin with interferon‑γ, or IL‑1 with interferon‑γ produced synergistic cytotoxic effects, suggesting these cytokines may directly mediate β‑cell destruction in type I diabetes.

Abstract

An assay was developed to detect the cytotoxic effects of cytokines on rat pancreatic islet cells in monolayer culture. Cell lysis was detected by a 51Cr-release assay after 4 days of incubation with various cytokines. When tested alone, murine (rat and mouse) interferon-gamma (mIFN-gamma) produced a small dose-dependent lysis of islet cells; human IFN-gamma, mouse IFN-alpha/beta, interleukins 1 and 2 (IL-1 and IL-2), tumor necrosis factor (TNF), and lymphotoxin (LT) were inactive. When added together, the following combinations of cytokines showed synergistic cytotoxic effects: TNF (or LT) plus IL-1, TNF (or LT) plus mIFN-gamma, and IL-1 plus mIFN-gamma. These results indicate that the cytokine products of mononuclear cells of the immune system, IFN-gamma, TNF, LT, and IL-1 have strong synergistic cytotoxic effects on islet cells and therefore may act as direct chemical mediators of islet beta-cell destruction in type I (insulin-dependent) diabetes.