Reactive oxygen species in tumor necrosis factor-alpha-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease.
The multifunctional cytokine tumor necrosis factor-alpha (TNF-alpha) 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-alpha-induced signaling pathways associated with certain inflammatory diseases, their role in TNF-alpha 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-alpha rapidly induces ROS generation, IkappaB degradation, NF-kappaB p65 nuclear translocation, and ultimately production of inflammatory cytokines; (ii) TNF-alpha-induced cytokine production is mediated both by the mammalian target of rapamycin signaling pathway via NF-kappaB activation and by ROS; (iii) TNF-alpha-dependent NF-kappaB activation (that is, IkappaB degradation and NF-kappaB 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-alpha-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.
Young
Chen N
CN
Department of Dermatology, Wayne State University School of Medicine, Detroit, Michigan, USA.
Koepke
Jay I
JI
EXT Life Sciences Inc., TechOne Building, Detroit, Michigan, USA.
Terlecky
Laura J
LJ
EXT Life Sciences Inc., TechOne Building, Detroit, Michigan, USA; Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA.
Borkin
Michael S
MS
Department of Dermatology, Wayne State University School of Medicine, Detroit, Michigan, USA.
Boyd
Savoy L
SL
Department of Dermatology, Wayne State University School of Medicine, Detroit, Michigan, USA.
Terlecky
Stanley R
SR
Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA. Electronic address: srterlecky@med.wayne.edu.
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000627:therapeutic use; D002374:Catalase / Q000627:therapeutic use; D002478:Cells, Cultured; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D011494:Protein Kinases / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D012871:Skin Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D058570:TOR Serine-Threonine Kinases; D013654:Taurine / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
D000975:Antioxidants; D016166:Free Radical Scavengers; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D013654:Taurine; D006861:Hydrogen Peroxide; D002374:Catalase; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000111:Acetylcysteine