Sj. Muga et al., 8S-lipoxygenase products activate peroxisome proliferator-activated receptor alpha and induce differentiation in murine keratinocytes, CELL GROWTH, 11(8), 2000, pp. 447-454
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, tr
ansgenic mice with 8-LOX targeted to keratinocytes through the use of a lor
icrin promoter were generated. Histological analyses showed that the skin,
tongue, and stomach of transgenic mice are highly differentiated, and immun
oblotting and immunohistochemistries of skin showed higher levels of kerati
n-1 expression compared with wild-type mice. The labeling index, however, o
f the transgenic epidermis was twice that of the wild-type epidermis, Furth
ermore, 8S-HETE treatment of wild-type primary keratinocytes induced kerati
n-1 expression. Peroxisome proliferator activated receptor alpha (PPAR alph
a) was identified as a crucial component of keratin-1 induction through tra
nsient transfection with expression vectors for PPAR alpha, PPAR gamma, and
a dominant-negative PPAR, as well as through the use of known PPAR agonist
s, 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 alpha.