Significance of leukotriene-A4 hydrolase in the pathogenesis of psoriasis.

Abstract

The 5-lipoxygenase (5-LO) product of arachidonic acid, leukotriene (LT-)B4, is considered to play a significant role in the pathogenesis of psoriasis. In vitro LTB4 is a potent chemoattractant for leukocytes, and it increases DNA synthesis in human cultured keratinocytes. Intradermal injection of LTB4 into human skin in vivo results in a wheal and flare reaction, and topical application produces intraepidermal microabscesses and induces hyperproliferation. Furthermore, LTB4 has been determined in biologically active amounts in psoriatic skin lesions. Despite the importance of LTB4 in psoriasis, the capacity of the human epidermis to synthesize LTB4 has remained controversial. Recently, a very limited 5-LO activity was reported in human epidermis. Thus, it was shown that human epidermis can contribute significantly to LT formation by transcellular LT synthesis. By this mechanism, LTA4 released from activated leukocytes is further transformed into LTB4 in the keratinocytes by the LTA4 hydrolase. Transcellular metabolism may be of importance in psoriasis where neutrophils migrate into the epidermis, because in human neutrophils the LTA4 hydrolase has been shown as the rate-limiting step in LTB4 formation. The LTA4 hydrolase was localized in the epidermis by activity determination, by inhibition of enzyme activity with known LTA4 hydrolase inhibitors, by Western blotting and by immunohistochemical staining. Moreover the enzyme was purified and further characterized from human cultured keratinocytes and human epidermis. Because of these recent results it is concluded that LTB4 is of significance in the pathogenesis of psoriasis, and it is suggested that future work should focus on developing potent LTA4 hydrolase inhibitors for treatment of psoriasis.