8S-lipoxygenase products activate peroxisome proliferator-activated receptor alpha and induce differentiation in murine keratinocytes.
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 alpha (PPARalpha) was identified as a crucial component of keratin-1 induction through transient transfection with expression vectors for PPARalpha, PPARgamma, 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 PPARalpha.
Muga
S J
SJ
University of Texas, M. D. Anderson Cancer Center, Science Park-Research Division, Smithville 78957, USA.
Thuillier
P
P
Pavone
A
A
Rundhaug
J E
JE
Boeglin
W E
WE
Jisaka
M
M
Brash
A R
AR
Fischer
S M
SM
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D015870:Gene Expression; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000502:physiology*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D007633:Keratins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D019076:Transgenes
D006893:Hydroxyeicosatetraenoic Acids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D007633:Keratins; C047628:8-hydroxyeicosatetraenoic acid; D001091:Arachidonate Lipoxygenases; C054192:arachidonate 8-lipoxygenase