IL-4 determines eicosanoid formation in dendritic cells by down-regulationof 5-lipoxygenase and up-regulation of 15-lipoxygenase 1 expression

Dendritic cell (DC) differentiation from human CD34(+) hematopoietic progen itor cells (HPCs) can be triggered in vitro by a combination of cytokines c onsisting of stem cell factor, granulocyte-macrophage colony-stimulating fa ctor, and tumor necrosis factor or. The immune response regulatory cytokine s, IL-4 and IL-13, promote DC maturation from HPCs, induce monocyte-DC tran sdifferentiation, and selectively up-regulate 15-lipoxygenase 1 (15-LO-1) i n blood monocytes. To gain more insight into cytokine-regulated eicosanoid production in DCs we studied the effects of IL-4/IL-13 on LO expression dur ing DC differentiation. In the absence of IL-4, DCs that had been generated from CD34(+) HPCs in response to stem cell factor/granulocyte-macrophage c olony-stimulating factor/tumor necrosis factor alpha expressed high levels of 5-LO and 5-LO activating protein. However, a small subpopulation of eosi nophil peroxidase(+) (EOS-PX) cells significantly expressed 15-LO-1,Additio n of IL-4 to differentiating DCs led to a marked and selective down-regulat ion of 5-LO but not of 5-LO activating protein in DCs and in EOS-PX+ cells and, when added at the onset of DC differentiation, also prevented 5-LO up- regulation. Similar effects were observed during IL-4- or IL-13-dependent m onocyte-DC transdifferentiation. Down-regulation of 5-LO was accompanied by up-regulation of 15-LO-1. yielding 15-LO-1(+) 5-LO-deficient DCs, However, transforming growth factor beta1 counteracted the IL-4-dependent inhibitio n of 5-LO but only minimally affected 15-LO-1 up-regulation. Thus, transfor ming growth factor beta1 plus IL-4 yielded large mature DCs that coexpress both LOs. Localization of 5-LO in the nucleus and of 15-LO-1 in the cytosol was maintained at all cytokine combinations in all DC phenotypes and in EO S-PX+ cells. In the absence of IL-4, major eicosanoids of CD34(+)-derived D Cs were 5S-hydroxyeicosatetraenoic acid (5S-HETE) and leukotriene B-4, wher eas the major eicosanoids of IL-4-treated DCs were 15S-HETE and 5S-15S-diHE TE. These actions of IL-4/IL-13 reveal a paradigm of eicosanoid formation c onsisting of the inhibition of one and the stimulation of another LO in a s ingle leukocyte lineage.