Regulation of Polymorphonuclear Leukocyte-Intestinal Epithelial Cell Interactions: Signalling Events and Potential Drug Targets

Paul      Hofman

Abstract

A crucial event in the inflammatory response is recruitment of polymorphonuclear leukocytes (PMNL) to a site of infection or injury. PMNL-epithelial interactions involve many fundamental cell processes, including adhesion, migration, secretion, phagocytosis and apoptosis. Thus, migration of PMNL across epithelial-lined organs is a primary event component of host defense. Moreover, PMNL transepithelial migration often results in disease symptoms. New insights into leukocyte-epithelial signalling mechanisms have emerged that are beginning to shed light on the role of many molecular interactions in regulating the rate of PMNL transepithelial migration. Knowledge of the basic mechanisms that control the activation of pro-inflammatory transcription factors, and how these innate immune signalling pathways lead to an activation of the adaptative immune response that maintains the chronically inflamed state, is essential for pharmacological manipulation of intestinal inflammation. This review highlights recent advances in our understanding of the different mechanisms of PMNL-epithelial cell adhesive interactions at the level of cell surface protein-protein binding events, and in intracellular signal transduction pathways that regulate the PMNL transepithelial migration. Finally, the potential modulation of these different signal pathways as possible therapeutic goals will be discussed.

Keywords: Intestinal epithelial cell, neutrophil, signalling, drugs, large bowel, Crohn'disease, ulcerative colitis, idiopathic inflammatory bowel diseases