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STAT3 modulates ?-cell cycling in injured mouse pancreas and protects against DNA damage.

ABSTRACT: Partial pancreatic duct ligation (PDL) of mouse pancreas induces a doubling of the ?-cell mass mainly through proliferation of pre-existing and newly formed ?-cells. The molecular mechanism governing this process is still largely unknown. Given the inflammatory nature of PDL and inflammation-induced signaling via the signal transducer and activator of transcription 3 (STAT3), the activation and the role of STAT3 in PDL-induced ?-cell proliferation were investigated. Duct ligation stimulates the expression of several cytokines that can act as ligands inducing STAT3 signaling and phosphorylation in ?-cells. ?-Cell cycling increased by conditional ?-cell-specific Stat3 knockout and decreased by STAT3 activation through administration of interleukin-6. In addition, the level of DNA damage in ?-cells of PDL pancreas increased after deletion of Stat3. These data indicate a role for STAT3 in maintaining a steady state in the ?-cell, by modulating its cell cycle and protection from DNA damage.

SUBMITTER: De Groef S

PROVIDER: S-EPMC5143397 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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STAT3 modulates β-cell cycling in injured mouse pancreas and protects against DNA damage.

De Groef S S Renmans D D Cai Y Y Leuckx G G Roels S S Staels W W Gradwohl G G Baeyens L L Heremans Y Y Martens G A GA De Leu N N Sojoodi M M Van de Casteele M M Heimberg H H

Cell death & disease 20160623 6

Partial pancreatic duct ligation (PDL) of mouse pancreas induces a doubling of the β-cell mass mainly through proliferation of pre-existing and newly formed β-cells. The molecular mechanism governing this process is still largely unknown. Given the inflammatory nature of PDL and inflammation-induced signaling via the signal transducer and activator of transcription 3 (STAT3), the activation and the role of STAT3 in PDL-induced β-cell proliferation were investigated. Duct ligation stimulates the ...[more]

PMID: 27336716

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Project description:Background and purposeWhite matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model.MethodsChronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis.ResultsDisruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post-bilateral carotid artery stenosis-induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720's effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling.ConclusionsOur study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.

Dataset Information

STAT3 modulates ?-cell cycling in injured mouse pancreas and protects against DNA damage.

Publications

STAT3 modulates β-cell cycling in injured mouse pancreas and protects against DNA damage.

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