Interleukin-12 (IL-12)/STAT4 Axis Is an Important Element for [beta]-Cell Dysfunction Induced by Inflammatory Cytokines

Pathology driving [beta]-cell loss in diabetes is poorly defined. Chronic subclinical inflammation is associated with [beta]-cell dysfunction. Acute in vitro exposure of islets and [beta]-cells to an inflammatory cytokine cocktail (IL-1[beta]/TNF-[alpha]/IFN-[gamma]) results in loss of cell function and viability. The contribution of each cytokine alone or in combination has been evaluated in homogeneous mouse [beta]-cell lines and primary mouse islets. Cytokine cooperation is required for [beta]-cell apoptosis with the most potent combinations including IL-1[beta]. Single cytokine exposure did not induce [beta]-cell apoptosis. Expression of endogenous interleukin-12 in [beta]-cells correlated with inflammatory cytokine combinations that induced [beta]-cell apoptosis. Uncoupling of the IL-12 axis by a block of IL-12 production, inhibition of IL-12 receptor/ligand interaction or disruption of IL-12 receptor signaling conferred protection to [beta]-cells from apoptosis induced by inflammatory cytokine stimulation. Signaling through STAT4 is indicated since disruption of IL-12 concomitantly reduced inflammatory cytokine stimulation of endogenous IFN-[gamma] expression. Primary mouse islets isolated from mice deficient in STAT4 show resistance to inflammatory-cytokine-induced cell death when compared to islets isolated from wild type mice. Collectively, the data identify IL-12 as an important mediator of inflammation induced [beta]-cell apoptosis. Modulation of IL-12/STAT4 signaling may be a valuable therapeutic strategy to preserve islet/[beta]-cell viability in established diabetes.