title: Interleukin-12 (IL-12)/STAT4 Axis Is an Important Element for β-Cell Dysfunction Induced by Inflammatory Cytokines.
abstract: 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 combinations including IL-1β. Single cytokine exposure did not induce β-cell apoptosis. Expression of endogenous interleukin-12 in β-cells correlated with inflammatory cytokine combinations that induced β-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 β-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-γ 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 β-cell apoptosis. Modulation of IL-12/STAT4 signaling may be a valuable therapeutic strategy to preserve islet/β-cell viability in established diabetes.
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Weaver
authors.affiliation: Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.|Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.|Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.|Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Taylor-Fishwick
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D016207:Cytokines / Q000502:physiology*; D018836:Inflammation Mediators / Q000502:physiology*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000503:physiopathology*; D051379:Mice; D050797:STAT4 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018932:Chemokine CCL2; D016207:Cytokines; D018836:Inflammation Mediators; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D018664:Interleukin-12