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

ABSTRACT: Pathology driving ?-cell loss in diabetes is poorly defined. Chronic subclinical inflammation is associated with ?-cell dysfunction. Acute in vitro exposure of islets and ?-cells to an inflammatory cytokine cocktail (IL-1?/TNF-?/IFN-?) results in loss of cell function and viability. The contribution of each cytokine alone or in combination has been evaluated in homogeneous mouse ?-cell lines and primary mouse islets. Cytokine cooperation is required for ?-cell apoptosis with the most potent combinations including IL-1?. Single cytokine exposure did not induce ?-cell apoptosis. Expression of endogenous interleukin-12 in ?-cells correlated with inflammatory cytokine combinations that induced ?-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 ?-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-? 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 ?-cell apoptosis. Modulation of IL-12/STAT4 signaling may be a valuable therapeutic strategy to preserve islet/?-cell viability in established diabetes.

SUBMITTER: Weaver JR

PROVIDER: S-EPMC4640700 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Weaver Jessica R JR Nadler Jerry L JL Taylor-Fishwick David A DA

PloS one 20151110 11

Pathology driving β-cell loss in diabetes is poorly defined. Chronic subclinical inflammation is associated with β-cell dysfunction. Acute in vitro exposure of islets and β-cells to an inflammatory cytokine cocktail (IL-1β/TNF-α/IFN-γ) results in loss of cell function and viability. The contribution of each cytokine alone or in combination has been evaluated in homogeneous mouse β-cell lines and primary mouse islets. Cytokine cooperation is required for β-cell apoptosis with the most potent comb ...[more]

PMID: 26555476

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Dataset Information

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

Publications

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

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