TNF-α Regulated MAdCAM-1 Expression in Pancreatic Microvessel Endothelium: A Possible Role for MAdCAM-1 in Pancreatitis?

Abstract

The Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1) is associated with active inflammatory bowel disease; however MAdCAM-1 expression in the pancreas has not been previously documented. This study investi- gated MAdCAM-1 expression during cerulein-induced pancreatitis, and examined MAdCAM-1 expression, regulation and function in cytokine-treated pancreatic endothelial cells. Acute pancreatitis was induced by serial injections of ce- rulein over 10h, at which point tissue samples were collected. Pancreas endothelial cells (PMEC) were prepared from H- 2Kb-tsA58 (Immortomouse) mice. MAdCAM-1 expression was examined by immunoblotting after cytokine (TNF-� , IL-� or IFN-� ) stimulation. 2 nd messages regulating MAdCAM-1 were studied by adding pharmacological blockers prior to cy- tokines. MAdCAM-1 dependent lymphocyte adhesion was monitored using � 4� 7-integrin expressing lymphocytes. In ce- rulein-pancreatitis, MAdCAM-1 was upregulated by 10h, and closely correlated with histopathology. In PMEC, only TNF-� induced MAdCAM-1 dose (0-20ng/ml) and time (>12h-48h) dependently. MAdCAM-1 expression was PKC, ty- rosine kinase, p38 MAPK, and NF-� B-PARP dependent. PMEC-lymphocyte adhesion was increased by TNF-� , and sig- nificantly reduced by MAdCAM-1 antibody. MAdCAM-1 is induced in the inflamed pancreas, and in TNF-� stimulated PMEC, and may represent a novel determinant of pancreatic-lymphocyte recruitment in inflammation. PMEC cells might provide a useful system to study mechanisms related to both acute and chronic pancreatitis.