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

Abstract

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 investigated 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 cerulein over 10h, at which point tissue samples were collected. Pancreas endothelial cells (PMEC) were prepared from H2Kb-tsA58 (Immortomouse) mice. MAdCAM-1 expression was examined by immunoblotting after cytokine (TNF-, ILor IFN-) stimulation. 2 nd messages regulating MAdCAM-1 were studied by adding pharmacological blockers prior to cytokines. MAdCAM-1 dependent lymphocyte adhesion was monitored using 4 7-integrin expressing lymphocytes. In cerulein-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, tyrosine kinase, p38 MAPK, and NF-B-PARP dependent. PMEC-lymphocyte adhesion was increased by TNF-, and significantly 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.

Role of Hydrogen Sulfide, Substance P and Adhesion Molecules in Acute Pancreatitis

“…Different adhesion molecules, such as vascular cell adhesion protein 1 (VCAM-1), intercellular adhesion molecules 1 (ICAM-1), vascular adhesion protein1 (VAP-1), Hyaluronan, and mucosal addressin in cell adhesion molecules (MAdCAM-1) have been reported in the inflammation of the pancreas, resulting in the progression of inflammatory disease [56][57][58][59][60].…”

“…ICAM-1 [41,[64][65][66][67][68] Important marker for early detection, key role in neutrophil migration VCAM-1 [55,[69][70][71] Important role in leukocytic migration MAdCAM-1 [54,60,72,73] Possible role in lymphocytic migration VAP-1 [56,74,75] Important role in leukocytic migration Hyaluronan or Hyaluronic acid [58,[76][77][78][79] Key role in interstitial edema, which leads to tissue necrosis Selectins [62,[80][81][82][83][84][85][86][87][88] Important for leukocyte recruitment…”

“…The expression of MAdCAM-1 on pancreatic vascular endothelium has been recorded in caerulein-induced acute pancreatitis. This suggests that MAdCAM-1 might play a role in the recruitment of lymphocytes, resulting in the exacerbation of both local injury and remote injury to multiple organs in acute pancreatitis [60]. Different reports suggest that the expression of MAdCAM-1 in pancreas is regulated via protein kinase C (PKC), mitogen-activated protein kinase (MAPK), NF-kB, etc., along the lines of other adhesion molecules in colitis and IBD [54,73].…”