1. ¹Department of Dermatology, Wayne State University School of Medicine, Detroit, Michigan, USA
2. ²EXT Life Sciences Inc., TechOne Building, Detroit, Michigan, USA
3. ³Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA

Correspondence: Dr Stanley R. Terlecky, Department of Pharmacology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, Michigan 48201, USA. E-mail: srterlecky@med.wayne.edu

⁴Current address: Department of Dermatology, John D. Dingell VA Medical Center, Detroit, Michigan, USA.

Received 15 November 2007; Revised 4 March 2008; Accepted 15 March 2008; Published online 8 May 2008.

Abstract

The multifunctional cytokine tumor necrosis factor- (TNF-) 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--induced signaling pathways associated with certain inflammatory diseases, their role in TNF- 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- rapidly induces ROS generation, IB degradation, NF-B p65 nuclear translocation, and ultimately production of inflammatory cytokines; (ii) TNF--induced cytokine production is mediated both by the mammalian target of rapamycin signaling pathway via NF-B activation and by ROS; (iii) TNF--dependent NF-B activation (that is, IB degradation and NF-B 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--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.