Tumor necrosis factor alpha-induced inflammation is increased but apoptosis is inhibited by common food additive carrageenan.

ABSTRACT: Tumor necrosis factor (TNF)-?, a homotrimeric, pleiotropic cytokine, is secreted in response to inflammatory stimuli in diseases such as rheumatoid arthritis and inflammatory bowel disease. TNF-? mediates both apoptosis and inflammation, stimulating an inflammatory cascade through the non-canonical pathway of NF-?B activation, leading to increased nuclear RelB and p52. In contrast, the common food additive carrageenan (CGN) stimulates inflammation through both the canonical and non-canonical pathways of NF-?B activation and utilizes the adaptor molecule BCL10 (B-cell leukemia/lymphoma 10). In a series of experiments, colonic epithelial cells and mouse embryonic fibroblasts were treated with TNF-? and carrageenan in order to simulate the possible effects of exposure to dietary CGN in the setting of a TNF-?-mediated inflammatory disease process. A marked increase in secretion of IL-8 occurred, attributable to synergistic effects on phosphorylated NF-?B-inducing kinase (NIK) in the non-canonical pathway. TNF-? induced the ubiquitination of TRAF2 (TNF receptor-associated factor 2), which interacts with NIK, and CGN induced phosphorylation of BCL10, leading to increased NIK phosphorylation. These results suggest that TNF-? and CGN in combination act to increase NIK phosphorylation, thereby increasing activation of the non-canonical pathway of NF-?B activation. In contrast, the apoptotic effects of TNF-?, including activation of caspase-8 and PARP-1 (poly(ADP-ribose) polymerase 1) fragmentation, were markedly reduced in the presence of CGN, and CGN caused reduced expression of Fas. These findings demonstrate that exposure to CGN drives TNF-?-stimulated cells toward inflammation rather than toward apoptotic cell death and suggest that CGN exposure may compromise the effectiveness of anti-TNF-? therapy.

SUBMITTER: Bhattacharyya S 

PROVIDER: S-EPMC2998126 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature