Discovery of mammalian tissue-derived peptides that induce tight junction formation

Tight junctions (TJs) are cell-cell adhesion structures that function as barriers between epithelial cells to avoid dehydration, regulate ion permeability and prevent invasion of bacteria and viruses. Disruption of TJs is causative of various inflammatory diseases including inflammatory bowel diseases (IBD), atopic dermatitis and asthma. We identified TJ-inducing small peptides from mouse peritoneum-conditioned medium. The peptides, which we designate junction-inducing peptide like a zipper (Jipper), are 35-40 residue peptides corresponding to the C-terminal region of alpha1-antitrypsin (A1AT), the serine protease inhibitor abundant in circulating blood. Both mouse and human synthetic Jippers, as well as the human A1AT C-terminal peptides cleaved by matrix metalloproteinases (MMPs), induces TJs at cell-cell boundary of epithelial cells. Our study identifies the TJ-inducing peptides in mammalian tissues, and provides a basis for a clinically relevant strategy against TJ barrier-disrupted diseases.