Human epidermis transforms exogenous leukotriene A₄ into peptide leukotrienes: possible role in transcellular metabolism

Leukotriene B₄ formation can take place by cell interaction between keratinocytes and neutrophils. Thus, keratinocytes without proven 5-lipoxygenase activity can transform neutrophil-derived leukotriene A₄ into leukotriene B₄. The purpose of the present study was to investigate whether human epidermis is able to transform leukotriene A₄ sequentially into the peptide leukotrienes (LTC₄, LTD₄ and LTE₄). Epidermis isolated using the suction blister technique or keratomed skin specimens were incubated with either neutrophils or exogenously added leukotriene A₄. Peptide leukotrienes were determined by integrated optical density after RP-HPLC separation, and the identity of leukotrine C₄ was confirmed by (1) the retention time similarity with authentic leukotriene C₄; (2) the UV spectrum determined with an on-line diode array detector; and (3) conversion by γ-glutamyl transpeptidase of the peak coeluting with authentic leukotriene C₄ into a new peak coeluting with authentic leukotriene D₄. The results of this study showed that while human epidermis cannot form detectable amounts of peptide leukotrienes by itself, it can transform exogenous leukotriene A₄ into peptide leukotrienes. Furthermore, coincubation of human epidermis and neutrophils resulted in a marked increase (90%) in peptide leukotriene formation when compared with neutrophils alone, indicating that human epidermis can transform neutrophil-derived leukotriene A₄ into peptide leukotrienes. These results indicate that human skin contains leukotriene C₄ synthase activity capable of producing significant amounts of leukotriene C₄ from leukotriene A₄, and that the keratinocytes may play a more active role in peptide leukotriene formation in the skin than previously thought. Because neutrophil migration into the epidermis can provide the keratinocytes with leukotriene A₄, transcellular leukotriene biosynthesis may be important for peptide-leukotriene synthesis during skin inflammation.