Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation

J. A. Sorelle, T. Itoh, H. Peng, M. A. Kanak, K. Sugimoto, S. Matsumoto, M. F. Levy, M. C. Lawrence, B. Naziruddin

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Aims/hypothesis: Beta cell death triggered by pro-inflammatory cytokines plays a central role in the pathogenesis of type 1 diabetes and loss of transplanted islets. The nuclear factor κB (NF-κB) signalling pathway is a key regulator of beta cell stress response, survival and apoptosis. Withaferin A (WA), a steroidal lactone derived from Withania somnifera, has been demonstrated to be a potent, safe, anti-inflammatory molecule that can inhibit NF-κB signalling. Therefore, we evaluated the ability of WA to protect mouse and human islets from the damaging effects of pro-inflammatory cytokines in vitro and following intraportal transplantation. Methods: Mouse and human islets were treated with a cytokine cocktail, and NF-κB activation was measured by immunoblots, p65 nuclear translocation and chromatin immunoprecipitation of p65-bound DNA. Intraportal transplantation of a marginal mass of syngeneic mouse islets was performed to evaluate the in vivo protective effect of WA. Results: Treatment with WA substantially improved islet engraftment of syngeneic islets (83% for infusion with 200 islets + WA; 0% for 200 islets + vehicle) in a mouse model of diabetes, compared with marginal graft controls with superior islet function in WA-treated mice confirmed by glucose tolerance test. Treatment of human and mouse islets with WA prevented cytokine-induced cell death, inhibited inflammatory cytokine secretion and protected islet potency. Conclusions: WA was shown to be a strong inhibitor of the inflammatory response in islets, protecting against cytokine-induced cell damage while improving survival of transplanted islets. These results suggest that WA could be incorporated as an adjunctive treatment to improve islet transplant outcome.

Original languageEnglish (US)
Pages (from-to)814-824
Number of pages11
JournalDiabetologia
Volume56
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

Keywords

  • Beta cell
  • Cytokine
  • Islet transplantation
  • NF-κB

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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