| First Author | Ulvmar MH | Year | 2009 |
| Journal | J Invest Dermatol | Volume | 129 |
| Issue | 11 | Pages | 2584-93 |
| PubMed ID | 19516260 | Mgi Jnum | J:157137 |
| Mgi Id | MGI:4430052 | Doi | 10.1038/jid.2009.126 |
| Citation | Ulvmar MH, et al. (2009) Timed NF-kappaB inhibition in skin reveals dual independent effects on development of HED/EDA and chronic inflammation. J Invest Dermatol 129(11):2584-93 |
| abstractText | We have shown earlier that inhibiting NF-kappaB activity in murine basal keratinocytes leads to hyperproliferation, inflammation, and cancer in a tumor necrosis factor receptor 1 (TNFR1)-dependent manner. We report here the outcomes of NF-kappaB abrogation at different stages of epidermal morphogenesis using a conditional IkappaBalpha transgenic mouse model. We find that blocking NF-kappaB during embryogenesis mimics the epidermal and glandular defects seen in the human disease hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA), independently of the inflammatory phenotype and TNFR1. The onset of transgene expression after birth correlates with nuclear exclusion of the NF-kappaB p50 subunit, hyperplasia, and development of a chronic inflammation initiated and dominated by macrophages. In this model, macrophages are important producers of the vascular endothelial growth factor A (VEGFA), whose inhibition attenuates the excessive angiogenesis otherwise observed. The inflammatory reaction requires the continuous suppression of NF-kappaB in keratinocytes, indicating that an immune cell attractant(s) is directly induced in response to NF-kappaB inhibition. As TNFalpha upregulation is a late event in this model, good candidates for such chemoattraction are the monocyte chemotactic proteins 1, 2, and 3 (MCP-1-2-3), which are upregulated in the epidermal compartment concomitantly with the onset of NF-kappaB inhibition. |
