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Toll-like Receptor 4 Mediates Induction of the Bcl10-NFκB-Interleukin-8 Inflammatory Pathway by Carrageenan in Human Intestinal Epithelial Cells

2008; Elsevier BV; Volume: 283; Issue: 16 Linguagem: Inglês

10.1074/jbc.m708833200

1083-351X

Sumit Bhattacharyya, Ravinder K. Gill, Mei Ling Chen, Fuming Zhang, Robert J. Linhardt, Pradeep K. Dudeja, Joanne K. Tobacman,

Antimicrobial Peptides and Activities

The sulfated polysaccharide carrageenan (CGN) induces activation of NFkappaB and interleukin 8 (IL-8) in human colonic epithelial cells through a pathway of innate immunity mediated by Bcl10 (B-cell CLL/lymphoma 10). In this report, we identify Toll-like receptor 4 (TLR4), a member of the family of innate immune receptors, as the surface membrane receptor for CGN in human colonic epithelial cells. Experiments with fluorescence-tagged CGN demonstrated a marked reduction in binding of CGN to human intestinal epithelial cells and to RAW 264.7 mouse macrophages, following exposure to TLR4 blocking antibody (HTA-125). Binding of CGN to 10ScNCr/23 mouse macrophages, which are deficient in the genetic locus for TLR4, was absent. Additional experiments with TLR4 blocking antibody and TLR4 small interfering RNAs showed 80% reductions in CGN-induced increases in Bcl10 and IL-8. Transfection with dominant-negative MyD88 plasmid demonstrated MyD88 dependence of the CGN-TLR4-triggered increases in Bcl10 and IL-8. Therefore, these results indicate that CGN-induced inflammation in human colonocytes proceeds through a pathway of innate immunity, perhaps related to the unusual alpha-1,3-galactosidic linkage characteristic of CGN, and suggest how dietary CGN intake may contribute to human intestinal inflammation. Because CGN is a commonly used food additive in the Western diet, clarification of its effects and mechanisms of action are vital to issues of food safety.