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VASCULAR BIOLOGY

Differential effects of NF-B and p38 MAPK inhibitors and combinations thereof on TNF-- and IL-1-induced proinflammatory status of endothelial cells in vitro

Joanna M. Kudo,¹ Johanna Westra,² Sigridur A. Ásgeirsdóttir,¹ Robbert J. Kok,³ Koen Oosterhuis,⁴ Marianne G. Rots,⁴ Jan P. Schouten,⁵ Pieter C. Limburg,² and Grietje Molema¹

¹Endothelial Cell and Vascular Drug Targeting Group, Medical Biology Section, Department of Pathology and Laboratory Medicine, ²Department of Rheumatology, ³Department of Pharmacokinetics and Drug Delivery, ⁴Department of Therapeutic Gene Modulation, and ⁵Department of Epidemiology and Bioinformatics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Submitted 17 December 2004 ; accepted in final form 14 June 2005

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- and IL-1 differentially affected the expression of these inflammatory genes. Combined treatment with TNF- and IL-1 resulted in nonadditive, additive, and even synergistic induction of expression of VCAM-1, IL-8, and IL-6, respectively. Overexpression of dominant-negative inhibitor B protein blocking NF-B signaling confirmed a major role of this pathway in controlling both TNF-- and IL-1-induced expression of most of the genes studied. Although dexamethasone exerted limited effects at 1 µM, the thioredoxin inhibitor MOL-294, which regulates the redox state of NF-B, mainly inhibited adhesion molecule expression. Its most pronounced effect was seen on VCAM-1 mRNA levels, especially in IL-1-activated endothelium. One micromolar RWJ-67657, an inhibitor of p38 MAPK activity, diminished TNF-- and IL-1-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 RWJ-67657 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 with 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.

inflammatory gene expression; anti-inflammatory drugs; pharmacology; combination treatment

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