Regulation of the β-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:478

Article

Ghiasi, Seyed Mojtaba¹  Dahllof, Mattias Sailing¹  Osmai, Yama¹  Osmai, Mirwais¹  Jakobsen, Kathrine Kronberg¹  Aivazidis, Alexander²  Tyrberg, Bjorn²  Perruzza, Lisa³  Prause, Michala Cecilie Burstein¹  Christensen, Dan Ploug¹  Fog-Tonnesen, Morten⁴  Lundh, Morten¹  Grassi, Fabio³  Chatenoud, Lucienne⁵  Mandrup-Poulsen, Thomas¹ 

[1] Univ Copenhagen, Fac Hlth & Med Sci, Dept Biomed Sci, Copenhagen, Denmark

[2] AstraZeneca, IMED Biotech Unit, Translat Sci Cardiovasc Renal & Metab, Gothenburg, Sweden

[3] Univ Svizzera Italiana, Inst Res Biomed, Bellinzona, Switzerland

[4] Novo Nordisk, Diabet Biol & Hagedorn Res Inst, Copenhagen, Denmark

[5] Univ Paris 05, INSERM, Hosp Necker Enfants Malad, Paris, France

关键词: ASC;    Inflammation;    Danger associated-molecular patterns;    Potassium;    Purinergic receptors;   

DOI  :  10.1016/j.mce.2018.08.001

来源: Elsevier

【 摘 要 】

beta-Cells may be a source of IL-1 beta that is produced as inactive pro-IL-1 beta and processed into biologically-active IL-1 beta by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the beta-cell inflammasomes. NLRP1-expression was upregulated in islet-cells from T2D-patients and by IL-1 beta + IFN gamma in INS-1 cells in a histone-deacetylase dependent manner. NLRP3 was downregulated by cytokines in INS-1 cells. NLRC4 was barely expressed and not regulated by cytokines. High extracellular K+ reduced cytokine-induced apoptosis and NO production and restored cytokine-inhibited accumulated insulin-secretion. Basal inflammasome expression was JNK1-3 dependent. Knock-down of the ASC interaction domain common for NLRP1 and 3 improved insulin secretion and ameliorated IL-1 beta and/or glucolipotoxicity-induced cell death and reduced cytokine-induced NO-production. Broad inflammasome-inhibition, but not NLRP3-selective inhibition, protected against IL-1 beta-induced INS-1 cell-toxicity. We suggest that IL-1 beta causes beta-cell toxicity in part by NLRP1 mediated caspase-l-activation and maturation of IL-1 beta leading to an autocrine potentiation loop.

【 授权许可】

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