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J. Biol. Chem., Vol. 279, Issue 31, 32633-32642, July 30, 2004

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Effects of Tumor Necrosis Factor- (TNF) in Epidermal Keratinocytes Revealed Using Global Transcriptional Profiling^*

Tomohiro Banno, Alix Gazel, and Miroslav Blumenberg¶||**

From the Departments of Dermatology and ^¶Biochemistry, and ^||The Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, New York 10016 and Department of Dermatology at the Institute of Clinical Medicine, Tsukuba University 1-1-1, Tennodai, Ibaraki 305-8575, Japan

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

Received for publication, January 20, 2004 , and in revised form, May 12, 2004.

^* This work was supported by National Institutes of Health Grant AR41850 and Grants-in-Aid 13770429 (to T. B.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. Tel.: 212-263-5924; Fax: 212-263-8752; E-mail: blumem01{at}med.nyu.edu.

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