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Pre‐incubation with interleukin‐4 mediates a direct protective effect against the loss of pancreatic β‐cell viability induced by proinflammatory cytokines

Loss of pancreatic β‐cells in type I diabetes is associated with an increase in T helper 1 (Th1) proinflammatory cytokines in the islet milieu, with a concomitant reduction in Th2 anti‐inflammatory cytokines. In animal models, manoeuvres designed to polarize Th1 responses towards Th2, particularly involving interleukin (IL)‐4, have been shown to protect against insulitis and diabetes. The aim of this study was to determine whether IL‐4 can exert a direct effect on β‐cell viability. The rat pancreatic β‐cell line, BRIN‐BD11, was used. IL‐4R mRNA expression was assayed by reverse transcription–polymerase chain reaction and DNA sequencing and protein expression measured using anti‐IL‐4R antibodies and confocal microscopy. Cells were pretreated in vitro with IL‐4, incubated with IL‐1β and interferon (IFN)‐γ and DNA fragmentation and nitrite production analysed by flow cytometry and Griess assay, respectively. Expression of type I (IL‐4R alpha and common γ‐chain) and type II (IL‐4R alpha, IL‐13R alpha‐1) IL‐4R mRNA transcripts, together with cell surface expression of IL‐4R, was demonstrated. Pre‐incubation with IL‐4 reduced significantly cell death induced by IL‐1β alone or by a combination of IL‐1β and IFN‐γ, although this was not accompanied by a reduced production of nitrite. The protective effect of IL‐4 was not seen when all three cytokines were added simultaneously. These results demonstrate, for the first time, expression of IL‐4 receptor components on rat pancreatic β‐cells and reveal a direct protective effect on the loss of viability mediated by proinflammatory cytokines when β‐cells are pre‐incubated with IL‐4.