Abstract 1022: TNFα-induced apoptosis is reduced, but inflammation is increased by combined exposure with common food additive carrageenan

Abstract

Abstract Tumor necrosis factor (TNF)-α, a homotrimeric, pleiotropic cytokine, mediates both apoptosis and inflammation. Following exposure to TNF-α, activation of caspases leads to apoptotic cell death and stimulation of an inflammatory cascade through the non-canonical pathway of NF-κB activation leads to increased nuclear RelB and p52. In contrast, the common food additive carrageenan (CGN), which contains sulfated galactose residues, stimulates inflammation through both the canonical and non-canonical pathways of NF-κB activation. CGN-induced inflammation utilizes B-cell leukemia/lymphoma (BCL)-10 to activate a pathway of innate immunity that is initiated by interaction with toll-like receptor (TLR)-4. CGN also stimulates inflammation through a reactive oxygen species-mediated pathway. In a series of cell-based experiments, colonic epithelial cells and mouse embryonic fibroblasts were treated with TNF-α and CGN, in order to simulate the possible effects of exposure to dietary CGN in the setting of TNF-α-mediated effects. Marked increase in secretion of Interleukin (IL)-8 occurred, attributable to synergistic effects on phospho-NIK in the non-canonical pathway. TNF-α induced the ubiquitination of TNF receptor-associated factor (TRAF)-2 which interacts with NFκB-inducing kinase (NIK), and CGN induced phosphorylation of BCL10, which is required for NIK-phosphorylation. These results suggest that TNF-α and CGN in combination act to increase NIK phosphorylation, thereby increasing activation of the non-canonical pathway of NF-κB activation. In contrast, the apoptotic effects of TNF-α, including activation of caspase-8 and poly [ADP-ribose] polymerase (PARP)-1 fragmentation, were markedly reduced in the presence of CGN. CGN exposure caused reduction in Fas by cDNA microarray and by ELISA. The study results demonstrate that exposure to CGN drives TNF-α stimulated cells toward inflammation, rather than toward apoptotic cell death. The findings suggest that CGN exposure may compromise the effectiveness of anti-TNF-α therapy. Average consumption of CGN in the typical Western diet is reported to be 250 mg/day, in contrast to therapeutic glycosides, such as digoxin that are prescribed in doses of ∼0.1 mg/day. Ingestion of CGN-containing foods has the potential to both inhibit the pro-apoptotic effect and to increase the pro-inflammatory effect of TNF-α and may contribute to malignant transformation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1022. doi:10.1158/1538-7445.AM2011-1022