Reactive oxygen species in tumor necrosis factor-α-activated primary human keratinocytes: Implications for psoriasis and inflammatory skin disease

Abstract

The multifunctional cytokine tumor necrosis factor-α (TNF-α) is known to play an important role in inflammatory and immunological responses in human skin. Although it has been documented that reactive oxygen species (ROS) are involved in TNF-α-induced signaling pathways associated with certain inflammatory diseases, their role in TNF-α signaling cascades has not been examined in primary human keratinocytes used as a model of inflammatory skin disease and psoriasis. Employing a series of in vitro and in cellulo approaches, we have demonstrated that in primary human keratinocytes (i) TNF-α rapidly induces ROS generation, IκB degradation, NF-κB p65 nuclear translocation, and ultimately production of inflammatory cytokines; (ii) TNF-α-induced cytokine production is mediated both by the mammalian target of rapamycin signaling pathway via NF-κB activation and by ROS; (iii) TNF-α-dependent NF-κB activation (that is, IκB degradation and NF-κB p65 nuclear translocation) is not mediated by ROS; and (iv) a cell-penetrating derivative of the antioxidant enzyme, catalase, as well as taurine and N-acetyl-cysteine attenuate the TNF-α-induced production of cytokines. These latter results suggest that catalase and perhaps other antioxidants should be considered as part of a more specific and effective therapy for the treatment of inflammatory skin diseases, including psoriasis. © 2008 The Society for Investigative Dermatology.