Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin (K) 5 or K14 genes. It is widely regarded as a mechanobullous disease, resulting from a weakened cytoskeleton, causing extensive cytolysis. It was postulated by others that certain K14 mutations induce tumor necrosis factor-α (TNF-α) and increase apoptosis. Here, we report that in K5^−/− mice and in a cell culture model of EBS, the mRNA and protein levels of TNF-α remain unaltered. Transcriptome analysis of K5^−/− mice revealed, however, that the proinflammatory cytokines IL-6 and IL-1β were significantly upregulated at the mRNA level in K5^−/− mouse skin. These results were confirmed by TaqMan real-time PCR and ELISA assays. We hypothesize that keratin mutations contribute to EBS in a mouse model by inducing local inflammation that mediates a stress response. Following clinical reports, we applied the small molecule doxycycline to K5^−/− mice. We demonstrate that doxycycline extended the survival of neonatal K5^−/− mice from less than 1 to up to 8 hours. Microarray and TaqMan real-time PCR showed a downregulation of matrix metalloproteinase 13 and IL-1β, indicating an effect of doxycycline on transcription. Our data offer a novel small molecule-based therapy approach for EBS.