Irritant dermatitis is a major cause of workplace injury. It affects individuals in a variety of work environments and is a source of significant morbidity and lost work time. The pathophysiology of irritant dermatitis is only poorly defined. Exposure of the skin to irritant chemicals results in the rapid appearance of the cardinal features of inflammation associated with cytokine activation and leukocyte infiltration. How irritants activate inflammation is not known. We believe that irritants may activate signaling pathways common to innate immune mechanisms. Centered in these pathways are transcription factors that are linked to pro-inflammatory cytokine genes, cell adhesion molecules, and proteins that trigger capillary leak. One key family of transcription factors linked to the activation of these diverse gene sets is the nuclear factor kappa B (NF-kB) family of transcription factors. Our hypothesis is that irritant exposure results in NF-kB activation in skin cells. This activation results in the triggering of a pro-inflammatory cascade and the clinical appearance of dermatitis. In order to test this hypothesis, we propose the following specific aims: 1) To examine whether irritants can activate NF-kB in cultured skin cells in vitro using epithelial and endothelial cells as targets. We will examine whether irritant treatment of cultured skin cells results in translocation of active NF-kB complexes from the cytoplasm to the nucleus; examine whether irritant treatment of HDMEC, HK, or HDF induces the phosphorylation and ubiquitination of IkBa, necessary steps for proteosome mediated degradation; examine whether translocated NF-kB complexes are capable of binding to relevant response elements of cytokine and cell adhesion molecule gene protomers. 2) To examine whether irritants can activate specific genes in cultured skin cells in vitro using epithelial and endothelial cells as targets. We will examine whether irritants induce or upregulate the expression of adhesion molecules ICAM-1 and E-selectin, and proinflammatory cytokines IL-8 and VEGF-C; examine whether irritants increase steady state mRNA expression of ICAM-1, E-selectin, IL-8, or VEGF-C; examine whether irritant treatment of cultured skin cells results in increase transcription of adhesion molecule or cytokine genes dependent upon NF-kB responsive elements. These studies will provide a framework to define the mechanisms by which irritants cause inflammation in the skin and provide a rational and mechanistic targets for prevention and treatment.
| White, Kellie J; Maffei, Vincent J; Newton-West, Marvin et al. (2011) Irritant activation of epithelial cells is mediated via protease-dependent EGFR activation. J Invest Dermatol 131:435-42 |
