Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory bowel disease.

Abstract

BACKGROUND & AIMS:

Junctional adhesion molecule-A (JAM-A) is localized at the tight junctions and controls leukocyte migration into the tissues. However, its functional role in inflammatory bowel disease (IBD) is unexplored.

METHODS:

Control, Crohn's disease (CD), and ulcerative colitis (UC) tissue specimens were studied for JAM-A expression, as well as the colon of mice given dextran sodium sulfate (DSS). Wild-type and JAM-A(-/-), Tie-2-Cre-JAM-A(-/-) (endothelial/hematopoietic-specific JAM inactivation) mice were studied for susceptibility to DSS. Disease activity and colonic inflammation were assessed using a disease activity index histology and endoscopy, and mucosal cytokines were measured by enzyme-linked immunosorbent assay. JAM-A function was investigated by RNA silencing in epithelial cells, and apoptosis was measured.

RESULTS:

In both CD and UC, as well as in experimental colitis, there is a loss of epithelial but not endothelial JAM-A expression. Deletion of JAM-A results in a dramatic increase in susceptibility to DSS colitis, as assessed by weight loss, disease activity index, histologic and endoscopic severity, and strikingly high mortality rates. This is not caused by the absence of JAM-A in the endothelial or hematopoietic compartments because Tie-2-Cre-JAM-A(-/-) mice are no more susceptible to DSS colitis than wild-type animals. JAM-A(-/-) mice displayed increased intestinal permeability and inflammatory cytokine production, and marked epithelial apoptosis. Silencing of JAM-A in intestinal epithelial cells resulted in increased permeability in vitro.

CONCLUSIONS:

Our results show a nonredundant and novel role of JAM-A in controlling mucosal homeostasis by regulating the integrity and permeability of epithelial barrier function.

• Authors: Stefania Vetrano, Maria Rescigno, Maria Rosaria Cera, Carmen Correale, Cristiano Rumio, Andrea Doni, Massimo Fantini, Andreas Sturm, Elena Borroni, Alessandro Repici, Massimo Locati, Alberto Malesci, Elisabetta Dejana, Silvio Danese
• Journal: Gastroenterology (Gastroenterology) Vol. 135 Issue 1 Pg. 173-84 (Jul 2008) ISSN: 1528-0012 [Electronic] United States
• PMID: 18514073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Cytokines
• F11R protein, human
• F11r protein, mouse
• Immunoglobulins
• Receptors, Cell Surface

Topics

• Animals
• Apoptosis
• Cell Adhesion Molecules (genetics, immunology, metabolism)
• Cell Movement (immunology)
• Colitis, Ulcerative (immunology, metabolism, pathology)
• Crohn Disease (immunology, metabolism, pathology)
• Cytokines (metabolism)
• Disease Models, Animal
• Down-Regulation (immunology)
• Gene Deletion
• Homeostasis (immunology)
• Humans
• Immunoglobulins (genetics, immunology, metabolism)
• Intestinal Mucosa (immunology, metabolism, pathology)
• Leukocytes (cytology, immunology)
• Male
• Mice
• Mice, Mutant Strains
• Permeability
• RNA Interference
• Receptors, Cell Surface (genetics, immunology, metabolism)