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

Identification of tumor necrosis factor-alpha (TNF alpha) as the key agent in inflammatory disorders, e.g. rheumatoid arthritis, Crohn's disease, and psoriasis, led to TNF alpha-targeting therapies, which, although avoiding many of the side-effects of previous drugs, nonetheless causes other si...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-07, Vol.279 (31), p.32633-32642
Main Authors: Banno, Tomohiro, Gazel, Alix, Blumenberg, Miroslav
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Apoptosis
Blotting, Northern
Cell Adhesion
Cell Death
Cell Division
Cell Lineage
Cell Movement
Cell Separation
Cells, Cultured
Cytoskeleton - metabolism
Flow Cytometry
Gene Expression Regulation
Humans
Inflammation
Keratinocytes - cytology
Keratinocytes - metabolism
Kinetics
Macrophages - metabolism
Microscopy, Fluorescence
Neutrophils - metabolism
NF-kappa B - metabolism
Oligonucleotide Array Sequence Analysis
RNA, Complementary - metabolism
Signal Transduction
Time Factors
Transcription, Genetic
Tumor Necrosis Factor-alpha - metabolism
Zinc Fingers
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Summary:Identification of tumor necrosis factor-alpha (TNF alpha) as the key agent in inflammatory disorders, e.g. rheumatoid arthritis, Crohn's disease, and psoriasis, led to TNF alpha-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, TNF alpha orchestrates the cutaneous responses to environmental damage and inflammation. To define TNF alpha action in epidermis, we compared the transcriptional profiles of normal human keratinocytes untreated and treated with TNF alpha for 1, 4, 24, and 48 h by using oligonucleotide microarrays. We found that TNF alpha regulates not only immune and inflammatory responses but also tissue remodeling, cell motility, cell cycle, and apoptosis. Specifically, TNF alpha regulates innate immunity and inflammation by inducing a characteristic large set of chemokines, including newly identified TNF alpha targets, that attract neutrophils, macrophages, and skin-specific memory T-cells. This implicates TNF alpha in the pathogenesis of psoriasis, fixed drug eruption, atopic and allergic contact dermatitis. TNF alpha promotes tissue repair by inducing basement membrane components and collagen-degrading proteases. Unexpectedly, TNF alpha induces actin cytoskeleton regulators and integrins, enhancing keratinocyte motility and attachment, effects not previously associated with TNF alpha. Also unanticipated was the influence of TNF alpha upon keratinocyte cell fate by regulating cell-cycle and apoptosis-associated genes. Therefore, TNF alpha 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 alpha effects and define the mechanisms and genes that achieve these outcomes, both of which are important for TNF alpha-targeted therapies.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M400642200