Cytokine-induced human islet cell death in vitro correlates with 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 from different 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-1 activation and the production of nitric oxide (NO). Rat RIN5AH and human islet cells were exposed to the cytokines IL-1β and IFN-γ and the NOS inhibitor aminoguanidine. Cell death, NO production, IκBα phosphorylation, p65 methylation, STAT-1 phosphorylation and cIAP-2 levels were 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. On the other hand, the human islet cells instead died by an NO-independent mechanism on day 3 and 5. This later occurring cell death was associated with a gradual decrease in IκBα phosphorylation and p65 methylation, and a lowered expression of the NF-κB target genes IκBα and cIAP-2. STAT-1 phosphorylation was persistently high during the entire cytokine exposure period in human islet cells. The results favor a pro-survival role of NF-κB and a pro-apoptotic role of STAT-1 in human islet cells. Thus, rodent insulin producing cells may not be suitable as models for human β-cells in the context of cytokine-induced damage.
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Henrietta
H
Hindlycke
Tao
T
Lu
Nils
N
Welsh
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000819:agonists / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D010766:Phosphorylation; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism*
D016207:Cytokines; D006146:Guanidines; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D009569:Nitric Oxide; C004479:pimagedine