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1 Division of Gastroenterology and Hepatology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA
2 Division of Gastroenterology and Hepatology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA; Digestive Disease Center, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwukee, WI, USA; Free Radical Research Center, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA
3 Department of Surgery, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA; Digestive Disease Center, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwukee, WI, USA
4 Division of Pediatric Surgery, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Surgery, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA; Free Radical Research Center, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: prafiee{at}mcw.edu.
Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a homing receptor preferentially expressed on gut-associated endothelial cells which plays a central role in leukocyte traffic into the mucosal immune compartment. Although the molecular mechanisms underlying endothelial ICAM-1 or E-selectin expression have been intensively investigated, the mechanisms which regulate human MAdCAM-1 expression have not been defined. Herein, we report MAdCAM-1 gene and protein expression in primary cultures of human intestinal microvascular endothelial cells (HIMEC) which was not demonstrated in human umbilical vein endothelial cells. Similar to ICAM-1 and E-selectin, MAdCAM-1 gene expression in HIMEC was inducible with TNF
, IL-1
or LPS activation. However, in striking contrast to ICAM-1and E-selectin, MAdCAM-1 mRNA and protein expression in HIMEC was heavily dependent on culture duration and/or cellular density, suggesting a prominent role for cell-cell interaction among these endothelial cells in the expression of the mucosal addressin. MAdCAM-1 expression was inhibited by both SN50 (NF
B inhibitor) and LY294002 (phosphatidylinositol 3 kinase (PI3K) inhibitor) whereas ICAM-1 and E-selectin expression was inhibited by SN50 but not by LY294002. The Akt phosphorylation by TNF or LPS was greater at higher cell density, demonstrating a similar pattern to MAdCAM-1 expression. NFB activation was not affected by cellular density in HIMEC. MAdCAM-1 expression in human gut endothelial cells is regulated by distinct signaling mechanisms involving both NFB and PI3K/Akt. These data also suggest that PI3K/Akt is involved in the gut specific differentiation of HIMEC, which results in expression of the mucosal addressin, MAdCAM-1.
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