The central observation in the induction of 15-LOX-1 by IL-4 was the delay in the mRNA synthesis. This can be attributed mainly to the kinetics of histone and STAT6 acetylation. The exact mechanisms for this process of gene regulation are however not clear. It would be interesting to study the kinetics of activation of other transcription factors and co-activators and their influence in this process. The expression of 15-LOX-1 is limited to very few cell types. This suggests that repressor mechanisms functioning in other cell types preventing the expression the enzyme. The next focus of research should be directed at elucidating such mechanisms, if at all they exist. This study would be important in understanding the mechanisms underlying the expression of 15-LOX-1 and its function in development.
With the advent of high throughput technology, attempt should be made to study the influence of 12/15-LOXs and its metabolites in various tissues and cell types. Automated cDNA micro-array technology offers such a possibility. This would add to our understanding of the role of these enzymes in the basic processes of the cell and shed light on potential roles in clinical disorders. Transgenic animals overexpressing 12/15-LOX in specific organs and tissues would greatly enhance our knowledge of diseases leading to the development of potential therapeutic strategies.
In this study, the participation of 12/15-LOXs in the apoptotic process in lung cells has been observed. PPARγ, a nuclear receptor plays an important role. Though, it is known that 12/15-LOX metabolites activate this receptor/transcription factor, the downstream targets of the factor are not known. The mechanism leading to activation of the death receptor also remains to be clarified. Antidiabetic thiazolidonenes are known activators of PPARγ and their involvement in the apoptotic process has tremendous therapeutic potential, especially in cancer chemotherapeutics.
Hepoxilins are a novel class of 12/15-LOX metabolites generally observed during the lack of or weakening of the antioxidant defence mechanism in the cell. The nature of influence they could have in the regulation of pro-oxidant enzymes is another interesting area of research. Another interesting aspect of study would be elucidation of the structural aspects of the hepoxilin synthase activity. Site-directed mutagenesis studies could be employed to clarify the mechanism of action.
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der Humboldt-Universität zu Berlin