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8S-Lipoxygenase Products Activate Peroxisome Proliferator-activated Receptor and Induce Differentiation in Murine Keratinocytes¹

University of Texas, M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957 [S. J. M., P. T., A. P., J. E. R., S. M. F.]; Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602 [W. E. B., M. J., A. R. B.]

To determine the function and mechanism of action of the 8S-lipoxygenase (8-LOX) product of arachidonic acid, 8S-hydroxyeicosatetraenoic acid (8S-HETE), which is normally synthesized only after irritation of the epidermis, transgenic mice with 8-LOX targeted to keratinocytes through the use of a loricrin promoter were generated. Histological analyses showed that the skin, tongue, and stomach of transgenic mice are highly differentiated, and immunoblotting and immunohistochemistries of skin showed higher levels of keratin-1 expression compared with wild-type mice. The labeling index, however, of the transgenic epidermis was twice that of the wild-type epidermis. Furthermore, 8S-HETE treatment of wild-type primary keratinocytes induced keratin-1 expression. Peroxisome proliferator activated receptor (PPAR) was identified as a crucial component of keratin-1 induction through transient transfection with expression vectors for PPAR, PPAR, and a dominant-negative PPAR, as well as through the use of known PPAR agonists. From these studies, it is concluded that 8S-HETE plays an important role in keratinocyte differentiation and that at least some of its effects are mediated by PPAR.

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