Tumor Necrosis Factor α-induced Inflammation Is Increased but Apoptosis Is Inhibited by Common Food Additive Carrageenan

Tumor necrosis factor (TNF)-alpha, a homotrimeric, pleiotropic cytokine, is secreted in response to inflammatory stimuli in diseases such as rheumatoid arthritis and inflammatory bowel disease. TNF-alpha mediates both apoptosis and inflammation, stimulating an inflammatory cascade through the non-canonical pathway of NF-kappa 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-kappa 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-alpha and carrageenan in order to simulate the possible effects of exposure to dietary CGN in the setting of a TNF-alpha-mediated inflammatory disease process. A marked increase in secretion of IL-8 occurred, attributable to synergistic effects on phosphorylated NF-kappa B-inducing kinase (NIK) in the non-canonical pathway. TNF-alpha 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-alpha and CGN in combination act to increase NIK phosphorylation, thereby increasing activation of the non-canonical pathway of NF-kappa B activation. In contrast, the apoptotic effects of TNF-alpha, 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-alpha-stimulated cells toward inflammation rather than toward apoptotic cell death and suggest that CGN exposure may compromise the effectiveness of anti-TNF-alpha/therapy.