Adenovirus-mediated expression of a mutant I kappa B kinase 2 inhibits theresponse of endothelial cells to inflammatory stimuli

In a variety of cell types, the transcription factor nuclear factor kappaB (NF-kappaB) functions as a mediator of stress and immune responses. In endo thelial cells (ECs), it controls the expression of genes encoding, eg, cyto kines, cell adhesion molecules, and procoagulatory proteins. This study inv estigates the effect of NF-kappaB suppression on several pathophysiologic f unctions of ECs, including inflammation, coagulation, and angiogenesis. A r ecombinant adenovirus was generated for expression of a dominant negative ( dn) mutant of I kappaB kinase 2 (IKK2), a kinase that acts as an upstream a ctivator of NF-kappaB, dnIKK2 inhibited NF-kappaB, resulting in strongly re duced nuclear translocation and DNA binding activity of the transcription f actor and lack of expression of several proinflammatory markers, including E-selectin, intercellular adhesion molecule 1, vascular cell adhesion molec ule 1, and interleukin-8. Concomitantly, inhibition of leukocyte binding to dnIKK2-expressing ECs could be demonstrated in a cell adhesion assay. Furt hermore, expression of tissue factor as well as the ability to form capilla ry tubes in a matrigel assay was impaired in dnIKK2-expressing ECs. These d ata demonstrate that NF-kappaB is of central importance not only for the in flammatory response but also for a number of other EC functions, Therefore, this transcription factor as well as its upstream regulatory signaling mol ecules may represent favorable targets for therapeutic interference. (Blood . 2001; 97:1611-1617) (C) 2001 by The American Society of Hematology.