Abstract
Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a 60-kDa endothelial cell adhesion glycoprotein that regulates lymphocyte trafficking to Peyer's patches and lymph nodes. Although it is widely agreed that MAdCAM-1 induction is involved in chronic gut inflammation, few studies have investigated regulation of MAdCAM-1 expression. We used two endothelial lines [bEND.3 (brain) and SVEC (high endothelium)] to study the signal paths that regulate MAdCAM-1 expression in response to tumor necrosis factor (TNF)-alpha using RT-PCR, blotting, adhesion, and immunofluorescence. TNF-alpha induced both MAdCAM-1 mRNA and protein in a dose- and time-dependent manner. This induction was tyrosine kinase (TK), p42/44, p38 mitogen-activated protein kinase (MAPK), and nuclear factor (NF)-kappa B/poly-ADP ribose polymerase (PARP) dependent. Because MAdCAM-1 is regulated via MAPKs, we examined mitogen/extracellular signal-regulated kinase (MEK)-1/2 activation in SVEC. We found that MEK-1/2 is activated by TNF-alpha within minutes and is dependent on TK and p42/44 MAPKs. Similarly, TNF-alpha activated NF-kappa B through TK, p42/44, p38 MAPKs, and PARP pathways in SVEC cells. MAdCAM-1 was also shown to be frequently distributed to endothelial junctions both in vitro and in vivo. Cytokines like TNF-alpha stimulate MAdCAM-1 in high endothelium via TK, p38, p42/22 MAPKs, and NF-kappa B/PARP. MAdCAM-1 expression requires NF-kappa B translocation through both direct p42/44 and indirect p38 MAPK pathways in high endothelial cells.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Alkaloids / pharmacology
-
Animals
-
Benzophenanthridines
-
Benzopyrans / pharmacology
-
Carbazoles*
-
Cell Adhesion Molecules
-
Cell Line, Transformed
-
Cysteine Proteinase Inhibitors / pharmacology
-
Endothelium / chemistry
-
Endothelium / cytology
-
Enzyme Inhibitors / pharmacology
-
Flavonoids / pharmacology
-
Fluorescent Antibody Technique
-
Gene Expression / drug effects
-
Gene Expression / physiology
-
Genistein / pharmacology
-
Imidazoles / pharmacology
-
Immunoglobulins / analysis*
-
Immunoglobulins / genetics*
-
In Vitro Techniques
-
Indoles*
-
Inflammatory Bowel Diseases / physiopathology
-
Intestinal Mucosa / chemistry*
-
Intestinal Mucosa / cytology*
-
Isoquinolines / pharmacology
-
Leupeptins / pharmacology
-
MAP Kinase Signaling System / drug effects
-
MAP Kinase Signaling System / physiology
-
Mice
-
Mucoproteins / analysis*
-
Mucoproteins / genetics*
-
NF-kappa B / antagonists & inhibitors
-
Phenanthridines / pharmacology
-
Pyridines / pharmacology
-
RNA, Messenger / analysis
-
Tumor Necrosis Factor-alpha / pharmacology
Substances
-
Alkaloids
-
Benzophenanthridines
-
Benzopyrans
-
Carbazoles
-
Cell Adhesion Molecules
-
Cysteine Proteinase Inhibitors
-
Enzyme Inhibitors
-
Flavonoids
-
GPI 6150
-
Imidazoles
-
Immunoglobulins
-
Indoles
-
Isoquinolines
-
Leupeptins
-
Madcam1 protein, mouse
-
Mucoproteins
-
NF-kappa B
-
Phenanthridines
-
Pyridines
-
RNA, Messenger
-
Tumor Necrosis Factor-alpha
-
KT 5823
-
Genistein
-
chelerythrine
-
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
-
benzyloxycarbonylleucyl-leucyl-leucine aldehyde
-
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one