In wound healing and many pathologic conditions, keratinocytes become activated: they turn into migratory, hyperproliferative cells that produce and secrete extracellular matrix components and signaling polypeptides. At the same time, their cytoskeleton is also altered by the production of specific keratin proteins. These changes are orchestrated by growth factors, chemokines, and cytokines produced by keratinocytes and other cutaneous cell types. The responding intracellular signaling pathways activate transcription factors that regulate expression of keratin genes. Analysis of these processes led us to propose the existence of a keratinocyte activation cycle, in which the cells first become activated by the release of IL-1. Subsequently, they maintain the activated state by autocrine production of proinflammatory and proliferative signals. Keratins K6 and K16 are markers of the active state. Signals from the lymphocytes, in the form of Interferon-gamma, induce the expression of K17 and make keratinocytes contractile. This enables the keratinocytes to shrink the provisional fibronectin-rich basement membrane. Signals from the fibroblasts, in the form of TGF-beta, induce the expression of K5 and K14, revert the keratinocytes to the healthy basal phenotype, and thus complete the activation cycle.

Identification of tumor necrosis factor-␣ (TNF␣) as the key agent in inflammatory disorders, e.g. rheumatoid arthritis, Crohn's disease, and psoriasis, led to TNF␣-targeting therapies, which, although avoiding many of the sideeffects of previous drugs, nonetheless causes other sideeffects, including secondary infections and cancer. By controlling gene expression, TNF␣ orchestrates the cutaneous responses to environmental damage and inflammation. To define TNF␣ action in epidermis, we compared the transcriptional profiles of normal human keratinocytes untreated and treated with TNF␣ for 1, 4, 24, and 48 h by using oligonucleotide microarrays. We found that TNF␣ regulates not only immune and inflammatory responses but also tissue remodeling, cell motility, cell cycle, and apoptosis. Specifically, TNF␣ regulates innate immunity and inflammation by inducing a characteristic large set of chemokines, including newly identified TNF␣ targets, that attract neutrophils, macrophages, and skinspecific memory T-cells. This implicates TNF␣ in the pathogenesis of psoriasis, fixed drug eruption, atopic and allergic contact dermatitis. TNF␣ promotes tissue repair by inducing basement membrane components and collagen-degrading proteases. Unexpectedly, TNF␣ induces actin cytoskeleton regulators and integrins, enhancing keratinocyte motility and attachment, effects not previously associated with TNF␣. Also unanticipated was the influence of TNF␣ upon keratinocyte cell fate by regulating cell-cycle and apoptosis-associated genes. Therefore, TNF␣ initiates not only the initiation of inflammation and responses to injury, but also the subsequent epidermal repair. The results provide new insights into the harmful and beneficial TNF␣ effects and define the mechanisms and genes that achieve these outcomes, both of which are important for TNF␣-targeted therapies.