title: Carboxylated glycans mediate colitis through activation of NF-kappa B.
abstract: The role of carbohydrate modifications of glycoproteins in leukocyte trafficking is well established, but less is known concerning how glycans influence pathogenesis of inflammation. We previously identified a carboxylate modification of N-linked glycans that is recognized by S100A8, S100A9, and S100A12. The glycans are expressed on macrophages and dendritic cells of normal colonic lamina propria, and in inflammatory infiltrates in colon tissues from Crohn's disease patients. We assessed the contribution of these glycans to the development of colitis induced by CD4(+)CD45RB(high) T cell transfer to Rag1(-/-) mice. Administration of an anti-carboxylate glycan Ab markedly reduced clinical and histological disease in preventive and early therapeutic protocols. Ab treatment reduced accumulation of CD4(+) T cells in colon. This was accompanied by reduction in inflammatory cells, reduced expression of proinflammatory cytokines and of S100A8, S100A9, and receptor for advanced glycation end products. In vitro, the Ab inhibited expression of LPS-elicited cytokines and induced apoptosis of activated macrophages. It specifically blocked activation of NF-kappaB p65 in lamina propria cells of colitic mice and in activated macrophages. These results indicate that carboxylate-glycan-dependent pathways contribute to the early onset of colitis.
authors.affiliation: Glycobiology Program, The Burnham Institute, La Jolla, CA 92037, USA. gsrikrishna@burnham.org
authors.forename: Geetha
authors.initials: G
authors.lastname: Srikrishna
authors.forename: Olga
authors.initials: O
authors.lastname: Turovskaya
authors.forename: Raziya
authors.initials: R
authors.lastname: Shaikh
authors.forename: Robbin
authors.initials: R
authors.lastname: Newlin
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.forename: Simon
authors.initials: S
authors.lastname: Murch
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
mesh_terms: D000818:Animals; D000906:Antibodies; D000938:Antigen-Presenting Cells / Q000502:physiology; D017209:Apoptosis / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D003092:Colitis / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004727:Endothelium / Q000166:cytology / Q000276:immunology / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000502:physiology; D007962:Leukocytes / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009088:Mucoproteins; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D011134:Polysaccharides / Q000276:immunology / Q000502:physiology*
chemical_list: D000906:Antibodies; D015815:Cell Adhesion Molecules; D016207:Cytokines; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D016328:NF-kappa B; D011134:Polysaccharides