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Neutralizing interleukin-1beta (IL-1beta) induces beta-cell survival by maintaining PDX1 protein nuclear localization.

ABSTRACT: The transcription factor PDX1 plays a critical role during ?-cell development and in glucose-induced insulin gene transcription in adult ?-cells. Acute glucose exposure leads to translocalization of PDX1 to the nucleoplasm, whereas under conditions of oxidative stress, PDX1 shuttles from the nucleus to the cytosol. Here we show that cytosolic PDX1 expression correlated with ?-cell failure in diabetes. In isolated islets from patients with type 2 diabetes and from diabetic mice, we found opposite regulation of insulin and PDX1 mRNA; insulin was decreased in diabetes, but PDX1 was increased. This suggests that elevated PDX1 mRNA levels may be insufficient to regulate insulin. In diabetic islets, PDX1 protein was localized in the cytosol, whereas in non-diabetic controls, PDX1 was in the nucleus. In contrast, overexpression of either IL-1 receptor antagonist or shuttling-deficient PDX1 restored ?-cell survival and function and PDX1 nuclear localization. Our results show that nuclear localization of PDX1 is essential for a functional ?-cell and provides a novel mechanism of the protective effect of IL-1 receptor antagonist on ?-cell survival and function.

SUBMITTER: Ardestani A

PROVIDER: S-EPMC3089558 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Neutralizing interleukin-1beta (IL-1beta) induces beta-cell survival by maintaining PDX1 protein nuclear localization.

Ardestani Amin A Sauter Nadine S NS Paroni Federico F Dharmadhikari Gitanjali G Cho Jae-Hyoung JH Lupi Roberto R Marchetti Piero P Oberholzer José J Conte Julie Kerr JK Maedler Kathrin K

The Journal of biological chemistry 20110310 19

The transcription factor PDX1 plays a critical role during β-cell development and in glucose-induced insulin gene transcription in adult β-cells. Acute glucose exposure leads to translocalization of PDX1 to the nucleoplasm, whereas under conditions of oxidative stress, PDX1 shuttles from the nucleus to the cytosol. Here we show that cytosolic PDX1 expression correlated with β-cell failure in diabetes. In isolated islets from patients with type 2 diabetes and from diabetic mice, we found opposite ...[more]

PMID: 21393239

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Project description:Duchenne muscular dystrophy (DMD) is a severe X-linked recessive muscle disorder caused by mutations in the dystrophin gene. Nonetheless, secondary processes involving perturbation of muscle regeneration probably exacerbate disease progression, resulting in the fatal loss of muscle in DMD patients. A dysfunction of undifferentiated myogenic cells is the most likely cause for the reduction of regenerative capacity of muscle. To clarify molecular mechanisms in perturbation of the regenerative capacity of DMD muscle, we have established several NCAM (CD56)-positive immortalized human dystrophic and non-dystrophic myogenic cell lines from DMD and healthy muscles. A pro-inflammatory cytokine, IL-1?, promoted cell cycle progression of non-dystrophic myogenic cells but not DMD myogenic cells. In contrast, IL-1? upregulated the Notch ligand Jagged1 gene in DMD myogenic cells but not in non-dystrophic myogenic cells. Knockdown of Jagged1 in DMD myogenic cells restored the IL-1?-promoted cell cycle progression. Conversely, enforced expression of Jagged1-blocked IL-1? promoted proliferation of non-dystrophic myogenic cells. In addition, IL-1? prevented myogenic differentiation of DMD myogenic cells depending on Jagged1 but not of non-dystrophic myogenic cells. These results demonstrate that Jagged1 induced by IL-1? in DMD myogenic cells modified the action of IL-1? and reduced the ability to proliferate and differentiate. IL-1? induced Jagged1 gene expression may be a feedback response to excess stimulation with this cytokine because high IL-1? (200-1000 pg/ml) induced Jagged1 gene expression even in non-dystrophic myogenic cells. DMD myogenic cells are likely to acquire the susceptibility of the Jagged1 gene to IL-1? under the microcircumstances in DMD muscles. The present results suggest that Jagged1 induced by IL-1? plays a crucial role in the loss of muscle regeneration capacity of DMD muscles. The IL-1?/Jagged1 pathway may be a new therapeutic target to ameliorate exacerbation of muscular dystrophy in a dystrophin-independent manner.

Dataset Information

Neutralizing interleukin-1beta (IL-1beta) induces beta-cell survival by maintaining PDX1 protein nuclear localization.

Publications

Neutralizing interleukin-1beta (IL-1beta) induces beta-cell survival by maintaining PDX1 protein nuclear localization.

Similar Datasets

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