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J. Biol. Chem., Vol. 275, Issue 41, 32077-32088, October 13, 2000

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Inflammatory Versus Proliferative Processes in Epidermis
TUMOR NECROSIS FACTOR  INDUCES K6b KERATIN SYNTHESIS THROUGH A TRANSCRIPTIONAL COMPLEX CONTAINING NFB AND C/EBP^*

Mayumi Komine^§¶, Laxmi S. Rao^¶, Takehiko Kaneko^§, Marjana Tomic-Canic, Kunihiko Tamaki^§, Irwin M. Freedberg, and Miroslav Blumenberg^**§§

From The Ronald O. Perelman  Department of Dermatology,  Departments of Cell Biology and ^** Biochemistry, and  Kaplan Comprehensive Cancer, New York University Medical Center, New York, New York 10016 and the ^§ Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan

Epidermal keratinocytes respond to injury by becoming activated, i.e. hyperproliferative, migratory, and proinflammatory. These processes are regulated by growth factors and cytokines. One of the markers of activated keratinocytes is keratin K6. We used a novel organ culture system to show that tumor necrosis factor  (TNF) induces the expression of K6 protein and mRNA in human skin. Multiple isoforms of K6 are encoded by distinct genes and have distinct patterns of expression. By having shown previously that proliferative signals, such as epidermal growth factor (EGF), induce expression of the cytoskeletal protein keratin K6b, we here demonstrate that the same isoform, K6b, is also induced by TNF, a proinflammatory cytokine. Specifically, TNF induces the transcription of the K6b gene promoter. By using co-transfection, specific inhibitors, and antisense oligonucleotides, we have identified NFB and C/EBP as the transcription factors that convey the TNF signal. Both transcription factors are necessary for the induction of K6b by TNF and act as a complex, although only C/EBP binds the K6b promoter DNA. By using transfection, site-directed mutagenesis, and footprinting, we have mapped the site that responds to TNF, NFB, and C/EBP. This site is separate from the one responsive to EGF and AP1. Our results show that the proinflammatory (TNF) and the proliferative (EGF) signals in epidermis separately and independently regulate the expression of the same K6b keratin isoform. Thus, the cytoskeletal responses in epidermal cells can be precisely tuned by separate proliferative and inflammatory signals to fit the nature of the injuries that caused them.

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