| First Author | Sehnert B | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 41 | Pages | 16556-61 |
| PubMed ID | 24062461 | Mgi Jnum | J:202312 |
| Mgi Id | MGI:5518476 | Doi | 10.1073/pnas.1218219110 |
| Citation | Sehnert B, et al. (2013) NF-kappaB inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-kappaB in immune-mediated diseases. Proc Natl Acad Sci U S A 110(41):16556-61 |
| abstractText | Activation of the nuclear transcription factor kappaB (NF-kappaB) regulates the expression of inflammatory genes crucially involved in the pathogenesis of inflammatory diseases. NF-kappaB governs the expression of adhesion molecules that play a pivotal role in leukocyte-endothelium interactions. We uncovered the crucial role of NF-kappaB activation within endothelial cells in models of immune-mediated diseases using a "sneaking ligand construct" (SLC) selectively inhibiting NF-kappaB in the activated endothelium. The recombinant SLC1 consists of three modules: (i) an E-selectin targeting domain, (ii) a Pseudomonas exotoxin A translocation domain, and (iii) a NF-kappaB Essential Modifier-binding effector domain interfering with NF-kappaB activation. The E-selectin-specific SLC1 inhibited NF-kappaB by interfering with endothelial IkappaB kinase 2 activity in vitro and in vivo. In murine experimental peritonitis, the application of SLC1 drastically reduced the extravasation of inflammatory cells. Furthermore, SLC1 treatment significantly ameliorated the disease course in murine models of rheumatoid arthritis. Our data establish that endothelial NF-kappaB activation is critically involved in the pathogenesis of arthritis and can be selectively inhibited in a cell type- and activation stage-dependent manner by the SLC approach. Moreover, our strategy is applicable to delineating other pathogenic signaling pathways in a cell type-specific manner and enables selective targeting of distinct cell populations to improve effectiveness and risk-benefit ratios of therapeutic interventions. |
