Effects of tumor necrosis factor-α (TNFα) in epidermal keratinocytes revealed using global transcriptional profiling

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