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Am J Physiol Cell Physiol (June 22, 2005). doi:10.1152/ajpcell.00620.2004
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Submitted on December 17, 2004
Accepted on June 14, 2005

Differential effects of NF-{kappa}B and p38 MAPK inhibitors and combinations thereof on TNF{alpha} and IL-1{beta} induced pro-inflammatory status of endothelial cells in vitro

Joanna M Kuldo1, Johanna Westra2, Sigridur A Asgeirsdottir1, Robbert J Kok3, Koen Oosterhuis4, Marianne G Rots4, Jan P Schouten5, Pieter C Limburg2, and Grietje Molema1*

1 Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2 Department of Rheumatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
3 Department of Pharmacokinetics and Drug Delivery, University of Groningen, Groningen, The Netherlands
4 Department of Therapeutic Gene Modulation, University of Groningen, Groningen, The Netherlands
5 Department of Epidemiology and Bioinformatics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

* To whom correspondence should be addressed. E-mail: g.molema{at}med.umcg.nl.

Endothelial cells actively participate in inflammatory events by regulating leukocyte recruitment via the expression of inflammatory genes such as E-selectin, VCAM-1, ICAM-1, IL-6, IL-8, and cyclooxygenase (COX)-2. In this study we showed by real time RT-PCR that activation of human umbilical vein endothelial cells (HUVEC) by TNF{alpha} and IL-1{beta} differentially affected the expression of these inflammatory genes. Combined treatment with TNF{alpha}/IL-1{beta} resulted in non-additive, additive, and even synergistic induction of expression of VCAM-1, IL-8, and IL-6, respectively. Overexpression of dominant negative (dn) I{kappa}B protein blocking NF-{kappa}B signalling confirmed a major role of this pathway in controlling both TNF{alpha} and IL-1{beta} induced expression of most of the genes studied. While dexamethasone (DEX) exerted limited effects at 1 µM, the thioredoxin inhibitor MOL-294 that regulates the redox state of NF-{kappa}B mainly inhibited adhesion molecule expression. Its most pronounced effect was seen on VCAM-1 mRNA levels, especially in IL-1{beta} activated endothelium. One µM RWJ67657, an inhibitor of p38 MAPK activity, diminished TNF{alpha} and IL-1{beta} induced expression of IL-6, IL-8, and E-selectin, but had little effect on VCAM-1 and ICAM-1. Combined treatment of HUVEC with MOL-294 and RWJ67657 resulted in significant blocking of the expression of E-selectin, IL-6, IL-8, and COX-2. The inhibitory effects were much stronger than those observed by single drug treatment. Application of combinations of drugs that affect multiple targets in activated endothelial cells may therefore be considered as a potential new therapeutic strategy to inhibit inflammatory disease activity.




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