Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress.
Apoptosis is probably the main form of beta-cell death in both type 1 diabetes mellitus (T1DM) and T2DM. In T1DM, cytokines contribute to beta-cell destruction through nuclear factor-kappaB (NF-kappaB) activation. Previous studies suggested that in T2DM high glucose and free fatty acids (FFAs) are beta-cell toxic also via NF-kappaB activation. The aims of this study were to clarify whether common mechanisms are involved in FFA- and cytokine-induced beta-cell apoptosis and determine whether TNFalpha, an adipocyte-derived cytokine, potentiates FFA toxicity through enhanced NF-kappaB activation. Apoptosis was induced in insulinoma (INS)-1E cells, rat islets, and fluorescence-activated cell sorting-purified beta-cells by oleate, palmitate, and/or cytokines (IL-1beta, interferon-gamma, TNFalpha). Palmitate and IL-1beta induced a similar percentage of apoptosis in INS-1E cells, whereas oleate was less toxic. TNFalpha did not potentiate FFA toxicity in primary beta-cells. The NF-kappaB-dependent genes inducible nitric oxide synthase and monocyte chemoattractant protein-1 were induced by IL-1beta but not by FFAs. Cytokines activated NF-kappaB in INS-1E and beta-cells, but FFAs did not. Moreover, FFAs did not enhance NF-kappaB activation by TNFalpha. Palmitate and oleate induced C/EBP homologous protein, activating transcription factor-4, and immunoglobulin heavy chain binding protein mRNAs, X-box binding protein-1 alternative splicing, and activation of the activating transcription factor-6 promoter in INS-1E cells, suggesting that FFAs trigger an endoplasmic reticulum (ER) stress response. We conclude that apoptosis is the main mode of FFA- and cytokine-induced beta-cell death but the mechanisms involved are different. Whereas cytokines induce NF-kappaB activation and ER stress (secondary to nitric oxide formation), FFAs activate an ER stress response via an NF-kappaB- and nitric oxide-independent mechanism. Our results argue against a unifying hypothesis for the mechanisms of beta-cell death in T1DM and T2DM.
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808 CP 618, B-1070 Brussels, Belgium.
Ilham
I
Kharroubi
Laurence
L
Ladrière
Alessandra K
AK
Cardozo
Zeynep
Z
Dogusan
Miriam
M
Cnop
Décio L
DL
Eizirik
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology*; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000633:toxicity*; D005434:Flow Cytometry; D007340:Insulinoma; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D019301:Oleic Acid / Q000633:toxicity; D010168:Palmitates / Q000633:toxicity; D010190:Pancreatic Neoplasms; D051381:Rats; D017208:Rats, Wistar; D019284:Thapsigargin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002273:Carcinogens; D016207:Cytokines; D005230:Fatty Acids, Nonesterified; D007375:Interleukin-1; D016328:NF-kappa B; D010168:Palmitates; D014409:Tumor Necrosis Factor-alpha; D019301:Oleic Acid; D019284:Thapsigargin; D007371:Interferon-gamma