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


RESULTS
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).
Steer
Sarah A
SA
The Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri, USA.
Scarim
Anna L
AL
Chambers
Kari T
KT
Corbett
John A
JA
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D004249:DNA Damage; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000503:physiopathology*; D004789:Enzyme Activation; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D050417:Insulin-Secreting Cells / Q000473:pathology*; D007340:Insulinoma / Q000473:pathology; D007375:Interleukin-1 / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D009336:Necrosis; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D024243:HMGB1 Protein; D007375:Interleukin-1; D009569:Nitric Oxide; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases