The broad long term objective of this study is to determine whether lipoxygenase activation in keratinocytes plays a role in the pathogenesis of inflammatory joint disease with which the skin diseases can often coexist. The more specific long-term goal is to assess the role of keratinocyte 15-lipoxygenase in the pathogenesis/expression of the inflammatory, dermatological and rheumatic disease, psoriasis. Material for study consists of cultured cells from normal epidermis, buccal mucous membrane, and from malignant human epidermal cell lines. The first focus of this present proposal is to discover whether the keratinocyte 15-lipoxygenase can be activated in a way which does not result in cell death, but does allow extracellular transfer of the hydroxylated polyunsaturated fatty acid derivatives. The next focus is to decide whether activation of this enzyme under other circumstances might also result in lethal damage to the keratinocyte. The next aspect of the present proposal is to explore the relation between activation of keratinocyte 15-lipoxygenase and the loss of capacity to esterify fatty acids and hydroxyeicosatetraenoic acids (HETES). To elucidate this latter area, the experimental design of the proposed work includes the examination of the pathways by which unsaturated fatty acids and hydroxy fatty acids form their Co A derivatives prior to incorporation into cellular lipids. In this regard, the primary questions to be asked are: whether there is a high affinity arachidonoyl Co A synthetase in cultured human keratinocytes, whether the hydroxy derivatives of the polyenoic acids are substrates for this enzyme, and whether damage to this enzyme or other enzymes in the pathway of esterification is associated with activation of 15-lipoxygenase. The next goal of this study is to analyze the structural characteristics of the unusual tetraenes which we have found to result from the metabolism of exogenous 5-HETE by the 15-lipoxygenase of membrane-damaged keratinocytes. The final component of this proposal is to determine whether activation of 15-lipoxygenase is associated with a modified keratinocyte response to the presence of cytokines which would be expected to be present at the site of an inflammatory reaction.