calpain and Inflammatory-Bowel-Diseases

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 5; Beclin-1; Calpain; Cell Differentiation; Colitis; Dextran Sulfate; Disease Models, Animal; Epithelial Cells; HMGB1 Protein; Humans; Inflammation; Inflammatory Bowel Diseases; Interleukin-10; Intestinal Mucosa; Mice; Mice, Knockout; Microtubule-Associated Proteins; Organoids

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.

Topics: Animals; Antigens, CD7; Apoptosis; Calpain; CD3 Complex; Cell Cycle; Cell Proliferation; Colitis; Galectin 4; Inflammatory Bowel Diseases; Integrin beta1; Intestinal Mucosa; Mice; Mice, Inbred BALB C; T-Lymphocyte Subsets; T-Lymphocytes