Pathway analysis of gene expression in local lymph nodes draining skin exposed to three different sensitizers.

Genomic analysis in the local lymph node assays (LLNAs) is useful for assessing skin sensitization of chemicals and providing insights into mechanisms of sensitization. In this study, we collected 1406 genes from previous microarray findings, validated changes in their expression by RT-PCR analysis in local lymph nodes draining skin exposed to different sensitizers, and interpreted their biological function through pathway-based genomic analysis, in which 468 genes were identified as being in the KEGG pathway database. The top-ranked functions (P < 0.01) identified as being affected by the sensitizers were associated with aspects of cell growth, such as DNA replication, cell cycle regulation and pyrimidine metabolism. All the sensitizers tested (DNCB, OXA and TDI) induced significant up-regulation of Psme4, which is associated with DNA replication; Tfdp1, which is related to cell cycle regulation; and Dut, which is involved in pyrimidine metabolism. Specific changes were also shown in functional categories related to the immune response, including cytokines and their receptors. Genes identified in these functional categories, such as Ccl21c, Cxcl9, Cxcl10, Ifng and Il12rb1, were found to have functional relevance. These findings may enhance our understanding and assessment of chemical sensitizers, and enable us to distinguish sensitizers from irritants and to classify chemicals as contact sensitizers.