The work is focussed on the regulation of 5-lipoxygenase enzyme expression and on the cellular physiology and pharmacology of 5-lipoxygenase. Recent data suggest that in addition to inflammatory diseases like asthma, psoriasis, inflammatory bowel disease and arthritis, the enzyme seems to be involved in cardiovascular diseases and cancer.

5-Lipoxygenase catalyzes the transformation of arachidonic acid to leukotriene A4. This unstable intermediate can be converted to leukotriene B4 by LTA4-hydrolase or to leukotriene C4 by LTC4-synthase. The capability to release leukotrienes is restricted to a few cell types like granulocytes and monocytes/macrophages. An experimental approach to study the mechanisms involved in the regulation of leukotriene biosynthesis are investigations on the development of 5-LO expression and activity during myeloid cell maturation. During cell differentiation by 1,25-dihydroxyvitamin D3 and transforming growth factor-beta (TGFß), myeloid cells and cell lines develop upregulate the 5-lipoxygenase pathway. Currently, the mechanism of the upregulation of the 5-lipoxygenase pathway by both agents and the role of DNA methylation in regulation of basal 5-lipoxygenase promoter activity is under investigation. This will help to understand the pharmacogenetic aspects of the 5-lipoxygenase pathway in atherosclerosis.

Another focus of the group are the cellular pathways involved in activation and repression of 5-lipoxygenase activity. We could show that 5-lipoxygenase is repressed by glutathione peroxidases and that it can be activated independently either by an increase in intracellular calcium concentration or via enzyme phosphorylation by the MAP kinases ERK1 and ERK2 at Ser630 and by MK2/3 at Ser271. In the Eicosanox integrated project, we will study the role of ligands to the 5-lipoxygenase C2 domain in the regulation of the cellular enzyme activity