Inhibitors of NFkB and Other Intracellular Signalling Pathways

1 Inhibitors of NFkB and Other Intracellular Signalling Pathways 

A more selective inhibition of NFkB can be achieved by transfecting cells with DNA coding for the natural inhibitor IkBo or a mutant IkB protein that lacks 36 N-terminal amino acids, and consequently becomes proteolysis resistant. In this way expression of adhesion molecules and monocyte adhesion and transmigration can be inhibited [87,88], The potentials and limitations of these latter types of therapy are however not fully understood as yet. Different transfection systems (adenoviral, retroviral, non-viral) are available for gene delivery purposes, all with their own potentials and restrictions. 

Inhibitors of IkBo phosphorylation have been described which irreversibly inhibit cytokine-induced phosphorylation without affecting constitutive phosphorylation. One such compound (Bay 11-7083 ((E)3-[4-f-butylphenyl)-sulfonyl]-2-propenenitrile)) was found to be effective in two animal models of inflammation after intraperitoneal administration [89]. In addition to the effect it has on the expression of adhesion molecules in pro-inflammatory responses, inhibition of the transcription factor NFkB will also have an effect on angiogenesis. Endothelial cells can produce growth factors and cytokines which have pro-angiogenic effects. Some of these factors, e.g. IL-8, TNFa and MCP-1 are known to be produced via NFkB-mediated endothelial cell activation [90,91]. The importance of NFKB-mediated responses in pro-angiogenic endothelium was reflected in studies in which the NFkB inhibitor PDTC decreased retinal neovascularization in the eye of mice [92]. 

It is anticipated that elucidation of the fine tuning of the regulatory processes in endothelial ceUs under pro-inflammatory conditions, will lead to the identification of additional novel pharmacological targets in the near future. 

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