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Carrageenan-induced innate immune response is modified by enzymes that hydrolyze distinct galactosidic bonds

Sumit Bhattacharyyaab, Haiying Liuc, Zhenqing Zhangc, Murielle Jamde, Pradeep K. Dudejaab, Gurvan Michelde, Robert J. Linhardtc, Joanne K. TobacmanabCorresponding Author Informationemail address

Received 13 April 2009; received in revised form 26 June 2009; accepted 2 July 2009. published online 30 October 2009.
Corrected Proof

Abstract 

The common food additive carrageenan (CGN) predictably induces intestinal inflammation in animal models. Mechanisms of CGN-induced nuclear factor κB and interleukin-8 (IL-8) stimulation include an immune-mediated pathway involving toll-like receptor 4 (TLR4) and B-cell lymphoma/leukemia 10 (BCL10) and a reactive oxygen species (ROS)-mediated pathway. To determine how the structure of CGN contributes to its initiation of inflammation through these two distinct mechanisms, we treated CGNs with galactosidases and carrageenases (CGNases) and determined the impact on IL-8 secretion and BCL10 production. Hydrolysis of CGN by the enzyme α-1→(3,6)-galactosidase significantly reduced increases in IL-8 and BCL10, but other galactosidases tested, including α-1→6-galactosidase, β-1→4-galactosidase and β-1→3,6-galactosidase, had no effect. In contrast, specific κ-CGNases or ι-CGNases, which hydrolyze β-1,4-galactosidic bonds, produced increases in IL-8 and BCL10 attributable to increased exposure of the immunogenic α-1→3-galactosidic epitope of CGN to TLR4. These results were consistent with induction of innate immune response by an interaction of TLR4 with the unusual α-d-Gal-(1→3)-d-Gal epitope present in CGN. Activation of the ROS-mediated pathway was unaffected by treatment of κ-CGN with either κ-CGNase (3 mg/L), α-1→(3,6)-galactosidase (20 mU/ml) or these enzymes in combination, indicating that changes in IL-8 production were attributable to the effects of induction of inflammation on the TLR4–BCL10-mediated innate immune pathway. These findings provide new information about the specificity of carbohydrate–protein interaction between CGN and TLR4 and may help to devise treatments that modify the immune reactivity induced by carbohydrate antigens.

a Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

b Jesse Brown VA Medical Center, Chicago, IL 60612, USA

c Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY, USA

d UPMC Univ Paris 06, UMR 7139 Marine Plants and Biomolecules, Station Biologique de Roscoff, F-29682 Roscoff, Bretagne, France

e CNRS, UMR 7139 Marine Plants and Biomolecules, Station Biologique de Roscoff, F-29682 Roscoff, Bretagne, France

Corresponding Author InformationCorresponding author. Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. Tel.: +1 312 569 7826 63; fax: +1 312 413 8283.

PII: S0955-2863(09)00152-1

doi:10.1016/j.jnutbio.2009.07.002

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