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- Title
HDAC inhibition protects pancreatic beta cells and islets from cytokine-induced cell death by disrupting NF-κB signaling.
- Authors
Fueger, Patrick T.; Hohmeier, Hans E.; Newgard, Christopher B.
- Abstract
Exposure of pancreatic beta cells to inflammatory cytokines such as interleukin-1β (IL-1β) and interferon-y (IFN-γ) activates the transcription of inducible nitric oxide (NO) synthase (iNOS), which leads to the production of NO and ultimately cell death. We have previously demonstrated that treatment of rat insulinoma (832/13) cells with the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) limits the production of NO and thereby prevents cell death upon exposure to inflammatory cytokines. Therefore, the aim was to determine the mechanism whereby HDAC inhibition prevents iNOS induction and resultant cytotoxicity in beta cells and to confirm these findings in rat islets. 832/13 cells were treated with 100 ng/ml TSA or vehicle and exposed to media with or without 10 ng/mL IL-1β and 100 U/mL IFN-γ for 24h, and cell viability was measured by MTS assay. Cytokine-mediated cell death was completely reversed by the addition of TSA. TSA decreased the expression of iNOS following exposure to cytokines, and nitrite accumulation (a measure of NO production) was lower in TSA- compared to vehicle-treated cells following cytokine treatment. Since nuclear localization of NF-κB is required for the induction of iNOS, we determined if TSA altered the translocation of NF-κB. Upon exposure to cytokines TSA is able to largely prevent the translocation of NF-κB from the cytoplasm to the nucleus thus abrogating iNOS induction. Importantly, these findings translate to primary rat islets, as TSA treatment ablates NO. production and minimizes cell death following exposure to IL-1β and IFN-γ. In summary, HDAC inhibition creates a NF-κB-dependent form of cytoprotection from inflammatory cytokines in pancreatic beta cells and islets, suggesting that the degree of acetylation of proteins may play an important role beta cell survival.
- Subjects
HISTONE deacetylase; PANCREATIC beta cells; ISLANDS of Langerhans tumors; CYTOKINES; CELL death; ACETYLATION; NITRIC oxide; LABORATORY rats
- Publication
FASEB Journal, 2007, Vol 21, Issue 6, pA833
- ISSN
0892-6638
- Publication type
Article