Upregulation of 8-lipoxygenase in the dermatitis of IkappaB-alpha-deficient mice.
Neonatal mice deficient in IkappaB-alpha, an inhibitor of the ubiquitous transcription factor NF-kappaB, develop severe and widespread dermatitis shortly after birth. In humans, inflammatory skin disorders such as psoriasis are associated with accumulation in the skin of the unusual arachidonic acid metabolite 12R-hydroxyeicosatetraenoic acid (12R-HETE), a product of the enzyme 12R-lipoxygenase. To examine the etiology of the murine IkappaB-alpha-deficient skin phenotype, we investigated the expression of lipoxygenases and the metabolism of exogenous arachidonic acid in the skin. In the IkappaB-alpha-deficient animals, the major lipoxygenase metabolite was 8S-HETE, formed together with a minor amount of 12S-HETE; 12R-HETE synthesis was undetectable. Skin from the wild-type littermates formed 12S-HETE as the almost exclusive lipoxygenase metabolite. Upregulation of 8S-lipoxygenase (8-LOX) in IkappaB-alpha-deficient mice was confirmed at the transcriptional and translational level using ribonuclease protection assay and western analysis. In immunohistochemical studies, increased expression of 8-LOX was detected in the stratum granulosum of the epidermis. In the stratum granulosum, 8-LOX may be involved in the terminal differentiation of keratinocytes. Although mouse 8S-lipoxygenase and human 12R-lipoxygenase are not ortholog genes, we speculate that in mouse and humans the two different enzymes may fulfill equivalent functions in the progression of inflammatory dermatoses.
Schneider
Claus
C
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA. claus.schneider@vanderbuilt.edu
Strayhorn
W David
WD
Brantley
Dana M
DM
Nanney
Lillian B
LB
Yull
Fiona E
FE
Brash
Alan R
AR
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001091:Arachidonate Lipoxygenases / Q000032:analysis* / Q000502:physiology; D016718:Arachidonic Acid / Q000378:metabolism; D015153:Blotting, Western; D003872:Dermatitis / Q000201:enzymology*; D006801:Humans; D020672:I-kappa B Proteins / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D012867:Skin / Q000378:metabolism; D015854:Up-Regulation
D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D016718:Arachidonic Acid; D001091:Arachidonate Lipoxygenases; D001092:Arachidonate 12-Lipoxygenase; C054192:arachidonate 8-lipoxygenase