HUMAN EPIDERMIS TRANSFORMS EXOGENOUS LEUKOTRIENE A(4) INTO PEPTIDE LEUKOTRIENES - POSSIBLE ROLE IN TRANSCELLULAR METABOLISM

Leukotriene B-4 formation can take place by cell interaction between k eratinocytes and neutrophils. Thus, keratinocytes without proven 5-lip oxygenase activity can transform neutrophil-derived leukotriene A(4) i nto leukotriene B-4. The purpose of the present study was to investiga te whether human epidermis is able to transform leukotriene A(4) seque ntially into the peptide leukotrienes (LTC(4), LTD(4) and LTE(4)). Epi dermis isolated using the suction blister technique or keratomed skin specimens were incubated with either neutrophils or exogenously added leukotriene A(4). Peptide leukotrienes were determined by integrated o ptical density after RP-HPLC separation, and the identity of leukotrin e C-4 was confirmed by (1) the retention time similarity with authenti c leukotriene C-4; (2) the UV spectrum determined with an on-line diod e array detector; and (3) conversion by gamma-glutamyl transpeptidase of the peak coeluting with authentic leukotriene C-4 into a new peak c oeluting with authentic leukotriene D-4. The results of this study sho wed that while human epidermis cannot form detectable amounts of pepti de leukotrienes by itself, it can transform exogenous leukotriene A(4) into peptide leukotrienes. Furthermore, coincubation of human epiderm is and neutrophils resulted in a marked increase (90%) in peptide leuk otriene formation when compared with neutrophils alone, indicating tha t human epidermis can transform neutrophil-derived leukotriene A(4) in to peptide leukotrienes. These results indicate that human skin contai ns leukotriene C-4 synthase activity capable of producing significant amounts of leukotriene C-4 from leukotriene A(4), and that the keratin ocytes may play a more active role in peptide leukotriene formation in the skin than previously thought. Because neutrophil migration into t he epidermis can provide the keratinocytes with leukotriene A(4), tran scellular leukotriene biosynthesis may be important for peptide-leukot riene synthesis during skin inflammation.