Role of 15S-lipoxygenase 2 in human corneal epithelium

Vanderbilt University, Nashville TN

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Abstract

Description: (Applicant's abstract) The arachidonic acid cascade, in particular the cyclooxgenase pathways, have been implicated the corneal epithelial cell proliferation. Recently, we have cloned a new human lipoxygenase, 15S-lipoxygenase-2, which is expressed in human tissue largely of epithelial component including the cornea. This is the second known human 15S-lipoxygenase. As implied by their names, the two human 15S-lipoxygenases make the same product, 15S-HETE. However, they exhibit significantly different catalytic activities and different product profiles; 15S-lipoxygenase-1 (1 5SLOX-1) catalyzes the formation of a mixture of products, 15S-HETE (80%) and 12S-HETE (20%). When the corneal epithelium from a noninflamed eye is incubated with arachidonic acid, the main the product formed is 15S-HETE indicating that 15-LOX-2 is the predominate pathway of arachidonic acid cascade in the normal cornea. Furthermore, our immuno-localization studies in human cornea have demonstrated 15-LOX-2 expression only in the basal layer of the epithelium and the in the limbal region, sites of mitotic activity. As the corneal epithelial becomes more terminally differentiated, there is a loss of 15-LOX-2 expression. These results taken together indicate that 15-LOX-2 also has a role in corneal epithelial cell proliferation and/or differentiation. Whether the cyclooxygenase pathways and the 15LOX-2 pathway function independently or are intertwined is not known. Potential common mediators are the peroxisome proliferator-activated receptor (PRAR). PPARs are inducible transcription factors, which have been described in the corneal epithelium and known to directly activate a number of genes involved in lipid homeostasis, inflammation, and epithelial cell differentiation. Products of 15-LOX-2 and cyclooxygenase have been shown to be natural ligands for PPARs. From these observations, we hypothesize that 15-LOX-2 is important in maintenance of the human cornea by regulation of epithelial cellular proliferation and/or differentiation and its effects are mediated by PPARs.