Galectin-4 controls intestinal inflammation by selective regulation of peripheral and mucosal T cell apoptosis and cell cycle.
Galectin-4 is a carbohydrate-binding protein belonging to the galectin family. Here we provide novel evidence that galectin-4 is selectively expressed and secreted by intestinal epithelial cells and binds potently to activated peripheral and mucosal lamina propria T-cells at the CD3 epitope. The carbohydrate-dependent binding of galectin-4 at the CD3 epitope is fully functional and inhibited T cell activation, cycling and expansion. Galectin-4 induced apoptosis of activated peripheral and mucosal lamina propria T cells via calpain-, but not caspase-dependent, pathways. Providing further evidence for its important role in regulating T cell function, galectin-4 blockade by antisense oligonucleotides reduced TNF-alpha inhibitor induced T cell death. Furthermore, in T cells, galectin-4 reduced pro-inflammatory cytokine secretion including IL-17. In a model of experimental colitis, galectin-4 ameliorated mucosal inflammation, induced apoptosis of mucosal T-cells and decreased the secretion of pro-inflammatory cytokines. Our results show that galectin-4 plays a unique role in the intestine and assign a novel role of this protein in controlling intestinal inflammation by a selective induction of T cell apoptosis and cell cycle restriction. Conclusively, after defining its biological role, we propose Galectin-4 is a novel anti-inflammatory agent that could be therapeutically effective in diseases with a disturbed T cell expansion and apoptosis such as inflammatory bowel disease.
Paclik
Daniela
D
Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Danese
Silvio
S
Berndt
Uta
U
Wiedenmann
Bertram
B
Dignass
Axel
A
Sturm
Andreas
A
D000818:Animals; D019011:Antigens, CD7 / Q000276:immunology; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D002154:Calpain / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D037541:Galectin 4 / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D019011:Antigens, CD7; D017252:CD3 Complex; D037541:Galectin 4; D019012:Integrin beta1; D002154:Calpain