Interleukin-12 (IL-12)/ XXXX Axis Is an Important Element for b-Cell Dysfunction Induced by Inflammatory Cytokines.

@entity17843 @entity32 @entity6 @entity19 @entity635 @entity2270 @entity637
UNASSIGNED: Pathology driving b-cell loss in @entity6 is poorly defined. Chronic subclinical @entity32 is associated with b-cell dysfunction. Acute in vitro exposure of islets and b-cells to an inflammatory cytokine cocktail ( @entity635 / @entity637 /IFN-y) results in loss of cell function and viability. The contribution of each cytokine alone or in combination has been evaluated in homogeneous @entity19 b-cell lines and primary @entity19 islets. Cytokine cooperation is required for b-cell apoptosis with the most potent combinations including @entity635 . Single cytokine exposure did not induce b-cell apoptosis. Expression of endogenous interleukin-12 in b-cells correlated with inflammatory cytokine combinations that induced b-cell apoptosis. Uncoupling of the IL-12 @entity2270 by a block of IL-12 production, inhibition of IL-12 receptor/ligand interaction or disruption of IL-12 receptor signaling conferred protection to b-cells from apoptosis induced by inflammatory cytokine stimulation. Signaling through @entity17843 is indicated since disruption of IL-12 concomitantly reduced inflammatory cytokine stimulation of endogenous IFN-y expression. Primary @entity19 islets isolated from @entity19 deficient in @entity17843 show resistance to inflammatory-cytokine-induced cell death when compared to islets isolated from wild type @entity19 . Collectively, the data identify IL-12 as an important mediator of @entity32 induced b-cell apoptosis. Modulation of IL-12/ @entity17843 signaling may be a valuable therapeutic strategy to preserve islet/b-cell viability in established @entity6 .
