Gene expression profiles and pathways in skin inflammation induced by three different sensitizers and an irritant.

It is often difficult to discriminate between chemically induced skin irritation and sensitization due to their similar clinical, pathological, and immunological responses. More information than that currently available from local lymph node assays (LLNAs), such as data from gene expression and pathway analysis, can provide more insightful data than the assay itself for distinguishing skin sensitization from skin irritation. This study investigated the gene expression profiles and pathways in ear skins of mice topically exposed daily for three consecutive days to the known strong contact sensitizer 1-chloro-2,4-dinitrobenzene, the skin contact sensitizer 2-phenyl-4-ethoxymethylene-5-oxazolone, the skin or respiratory sensitizer toluene 2,4-diisocyanate, or to the non-sensitizing irritant croton oil. All the sensitizers induced histological changes in ear tissues similar to those induced by the croton oil. In gene expression microarrays, sensitizers up-regulated 193 genes and down-regulated 61 genes in ear skin following chemical exposure. 13 genes whose expression was affected by more than two-fold by all three of the sensitizers, but not by the irritant, were selected by microarray analysis. Microarray and real-time RT-PCR analyses revealed that, of these genes, the allergic inflammation-related genes Oasl2 and Zbp1 were up-regulated in skin inflammation by the sensitizers. In gene expression pathway analysis of all the sensitizers and the croton oil, the top functions of the 48 genes were related to cytokine and cytokine receptors interactions, and only two genes (Cxcl9 and Cxcl10) were specific to skin sensitizer-induced skin inflammation. Thus, although contact sensitizer-induced skin inflammation is similar to irritant-induced responses in terms of histological changes and gene expression profiles, the regulation of allergic inflammation-related gene transcripts, such as those of Oasl2 and Zbp1 or Cxcl9 and Cxcl10, could help to discriminate skin sensitization from chemically induced skin inflammation.