Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1843, Issue 12, Pages 3038-3046Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2014.09.015
Keywords
Inflammasome; Autophagy; Protasome; Retinal pigment epithelium
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Funding
- Academy of Finland
- Paivikki and Sakari Sohlberg Foundation
- Orion-Farmos Research Foundation
- Finnish Cultural Foundation
- CIMO
- COST Actions [CM1001, TD1304]
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Retinal pigment epithelium (RPE) plays a major role in the maintenance of photoreceptors, and degeneration of RPE results in the development of age-related macular degeneration (AMD). Accumulation of intracellular protein aggregates, increased oxidative stress, and chronic inflammation are all factors damaging the functionality of aged RPE cells. Here, we report that inhibition of proteasomal degradation with MG-132 and autophagy with bafilomycin A1 resulted in the release of IL-1 beta but not that of IL-18 in human ARPE-19 cells. NLRP3 receptor became upregulated, and caspase-1, the functional component of an inflammasome complex, was activated. In addition to accumulating intracellular protein aggregates, inhibition of degradation systems induced oxidative stress which was demonstrated by elevated amounts of intracellular 4-hydroxynonenal (HNE)-protein adducts. Along with IL-1 beta, exposure to MG-132 and bafilomycin A1 resulted in the secretion of IL-8.A low concentration (1 pg/ml) of IL-1 beta was capable of triggering significant IL-8 production which also became attenuated by treatment with a specific caspase-1 inhibitor. These results suggest that decline in intracellular degradation systems results not only in increased amounts of intracellular protein aggregates and oxidative stress but also in the activation of NLRP3 inflammasomes, arisen as a result of elevated production of biologically active IL-1 beta. (C) 2014 Elsevier B.V. All rights reserved.
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