TNF-alpha induced endothelial MAdCAM-1 expression is regulated by exogenous, not endogenous nitric oxide.
BACKGROUND
MAdCAM-1 is an adhesion molecule expressed in Peyer's patches and lymphoid tissues which is mobilized by cytokines like TNF-alpha and is a major determinant of lymphocyte trafficking to the gut in human inflammatory bowel disease (IBD). It has been suggested that both reactive oxygen and nitrogen metabolites participate in regulating adhesion molecule expression in response to TNF-alpha.


METHODS
To examine how exogenous and endogenous sources of NO modulate MAdCAM-1 induction by TNF-alpha, we pre-treated mouse lymphatic endothelial cells with either long or short acting NO donors prior to TNF-alpha-stimulation, and measured MAdCAM-1 induction at 24 h.


CONCLUSIONS
DETA-NO, a long-acting NO donor, and SperNO, a rapid releasing NO donor both inhibited TNF-alpha-stimulated MAdCAM-1 expression in a concentration dependent manner. Both NO donors also reduced a4b7-dependent lymphocyte endothelial adhesion. Inhibition of endogenous NO production by either L-NAME, a non-selective NOS inhibitor, or by 1400 w, a selective iNOS inhibitor failed to induce, or potentiate TNF-alpha regulated MAdCAM-1 expression.


CONCLUSIONS
Exogenous NO donors may be beneficial in the treatment of IBD, while endogenous nitric oxide synthases may be less effective in controlling adhesion molecule expression in response to cytokines.
Oshima
T
T
Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, Louisiana, USA. toshim@lsumc.edu
Jordan
P
P
Grisham
M B
MB
Alexander
J S
JS
Jennings
M
M
Sasaki
M
M
Manas
K
K
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D004727:Endothelium / Q000166:cytology; D015151:Immunoblotting; D007136:Immunoglobulins / Q000096:biosynthesis / Q000187:drug effects*; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D051379:Mice; D009088:Mucoproteins / Q000096:biosynthesis / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009589:Nitrogen Oxides; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014226:Triazenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D000578:Amidines; D001596:Benzylamines; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D014226:Triazenes; D014409:Tumor Necrosis Factor-alpha; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase