Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1

PLoS Med. 2006 Feb;3(2):e17. doi: 10.1371/journal.pmed.0030017. Epub 2005 Dec 20.


Background: There are at least two phases of beta-cell death during the development of autoimmune diabetes: an initiation event that results in the release of beta-cell-specific antigens, and a second, antigen-driven event in which beta-cell death is mediated by the actions of T lymphocytes. In this report, the mechanisms by which the macrophage-derived cytokine interleukin (IL)-1 induces beta-cell death are examined. IL-1, known to inhibit glucose-induced insulin secretion by stimulating inducible nitric oxide synthase expression and increased production of nitric oxide by beta-cells, also induces beta-cell death.

Methods and findings: To ascertain the mechanisms of cell death, the effects of IL-1 and known activators of apoptosis on beta-cell viability were examined. While IL-1 stimulates beta-cell DNA damage, this cytokine fails to activate caspase-3 or to induce phosphatidylserine (PS) externalization; however, apoptosis inducers activate caspase-3 and the externalization of PS on beta-cells. In contrast, IL-1 stimulates the release of the immunological adjuvant high mobility group box 1 protein (HMGB1; a biochemical maker of necrosis) in a nitric oxide-dependent manner, while apoptosis inducers fail to stimulate HMGB1 release. The release of HMGB1 by beta-cells treated with IL-1 is not sensitive to caspase-3 inhibition, while inhibition of this caspase attenuates beta-cell death in response to known inducers of apoptosis.

Conclusions: These findings indicate that IL-1 induces beta-cell necrosis and support the hypothesis that macrophage-derived cytokines may participate in the initial stages of diabetes development by inducing beta-cell death by a mechanism that promotes antigen release (necrosis) and islet inflammation (HMGB1 release).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 3
  • Caspases / metabolism
  • Cell Culture Techniques
  • DNA Damage
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / physiopathology*
  • Enzyme Activation
  • HMGB1 Protein / metabolism*
  • Humans
  • Inflammation
  • Insulin-Secreting Cells / pathology*
  • Insulinoma / pathology
  • Interleukin-1 / physiology*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / pathology
  • Macrophages / immunology
  • Necrosis
  • Nitric Oxide / physiology*
  • Rats
  • Rats, Sprague-Dawley


  • HMGB1 Protein
  • Interleukin-1
  • Nitric Oxide
  • CASP3 protein, human
  • Casp3 protein, rat
  • Caspase 3
  • Caspases