title: The role of MAPK in governing lymphocyte adhesion to and migration across the microvasculature in inflammatory bowel disease.
abstract: Lymphocyte recruitment is a key pathogenic event in inflammatory bowel disease (IBD). Adhesion of T cells to human intestinal microvascular endothelial cells (HIMEC) is mediated by ICAM-1, VCAM-1 and fractalkine (FKN), but the signaling molecules that orchestrate this process have yet to be identified. Because MAPK play an important role in the response of many cell types to pro-inflammatory stimuli, we assessed the functional role of p38 MAPK, p42/44 MAPK and JNK in the regulation of lymphocyte adhesion to and chemotaxis across the microvasculature in IBD. We found that the MAPK were phosphorylated in the bowel microvasculature and human intestinal fibroblasts of patients with IBD but not of healthy individuals. Stimulation of HIMEC with TNF-alpha triggered phosphorylation of the MAPK, and up-regulation of VCAM-1, FKN and ICAM-1. Blockade of p38 decreased the expression of all MAPK by 50% (p<0.01), whereas inhibition of p42/44 decreased the expression of ICAM-1 and FKN by 50% (p<0.01). Treatment of human intestinal fibroblasts with TNF-alpha elicited production of IL-8 and MCP-1, which was reduced (p<0.05) by blockade of p38 and p42/44. Finally, blockade of p38 and p42/44 reduced lymphocyte adhesion to (p<0.05) and transmigration across (p<0.05) HIMEC monolayers. These findings suggest a critical role for MAPK in governing lymphocyte influx into the gut in IBD patients, and their blockade may offer a molecular target for blockade of leukocyte recruitment to the intestine.
authors.affiliation: Istituto Clinico Humanitas-IRCCS in Gastroenterology, University of Milan, Rozzano, Milan.
authors.forename: Franco
authors.initials: F
authors.lastname: Scaldaferri
authors.forename: Miquel
authors.initials: M
authors.lastname: Sans
authors.forename: Stefania
authors.initials: S
authors.lastname: Vetrano
authors.forename: Carmen
authors.initials: C
authors.lastname: Correale
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arena
authors.forename: Nico
authors.initials: N
authors.lastname: Pagano
authors.forename: Giacomo
authors.initials: G
authors.lastname: Rando
authors.forename: Fabio
authors.initials: F
authors.lastname: Romeo
authors.forename: Angelo E
authors.initials: AE
authors.lastname: Potenza
authors.forename: Alessandro
authors.initials: A
authors.lastname: Repici
authors.forename: Alberto
authors.initials: A
authors.lastname: Malesci
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054428:Chemokine CX3CL1 / Q000276:immunology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D055806:Microvessels / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4