Cytokine-induced human islet cell death in vitro correlateswith a persistently high phosphorylation of STAT-1, but not with NF-κB activation

• Studies of insulin producing β-cells have reported conflicting responses to NF-κB activation,encompassing both pro- and anti-apoptotic effects, possibly reflecting the use of β-cells fromdifferent species. Therefore, the aim of this study was to compare the temporal activation of NF-κB in rat and human insulin producing cells and relate this to the dynamics of cell death, STAT-1activation and the production of nitric oxide (NO). Rat RIN5AH and human islet cells wereexposed to the cytokines IL-1β and IFN-γ and the NOS inhibitor aminoguanidine. Cell death, NOproduction, ΙκΒα phosphorylation, p65 methylation, STAT-1 phosphorylation and cIAP-2 levelswere analyzed at different time-points. Cytokine-induced RIN5AH cell death occurred on day 1,and this was paralleled by NF-κB activation, STAT-1 phosphorylation and production of NO. Onthe other hand, the human islet cells instead died by an NO-independent mechanism on day 3and 5. This later occurring cell death was associated with a gradual decrease in ΙκΒα phosphorylation and p65 methylation, and a lowered expression of the NF-κB target genes ΙκΒα and cIAP-2. STAT-1 phosphorylation was persistently high during the entire cytokine exposureperiod in human islet cells. The results favor a pro-survival role of NF-κB and a pro-apoptoticrole of STAT-1 in human islet cells. Thus, rodent insulin producing cells may not be suitable asmodels for human β-cells in the context of cytokine-induced damage.

Nyckelord

Human islets

Apoptosis

NF-kappa B

STAT-1

Cytokines

Nitric oxide

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