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- Pergola, C, et al.
(författare)
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ERK-mediated regulation of leukotriene biosynthesis by androgens: a molecular basis for gender differences in inflammation and asthma
- 2008
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 105:50, s. 19881-19886
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Tidskriftsartikel (refereegranskat)abstract
- 5-Lipoxygenase initiates the biosynthesis of leukotrienes, lipid mediators involved in normal host defense and in inflammatory and allergic disorders. Despite an obvious gender bias in leukotriene-related diseases (e.g., asthma), gender aspects have been neglected in studies on leukotrienes and 5-lipoxygenase. Here, we show that leukotriene formation in stimulated whole blood or neutrophils from males is substantially lower compared with females, accompanied by changed 5-lipoxygenase trafficking. This is due to gender-specific differential activation of extracellular signal-regulated kinases (ERKs). The differences are directly related to variant male/female testosterone plus 5α-dihydrotestosterone levels, and addition of 5α-dihydrotestosterone to female blood or neutrophils reduced the high (female) LT biosynthesis capacity to low (male) levels. In conclusion, regulation of ERKs and leukotriene formation by androgens constitutes a molecular basis for gender differences in the inflammatory response, and in inflammatory diseases such as asthma.
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- Uebbing, S, et al.
(författare)
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Modulation of microRNA processing by 5-lipoxygenase
- 2021
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - 1530-6860. ; 35:2, s. e21193-
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Tidskriftsartikel (refereegranskat)
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- Werz, O, et al.
(författare)
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Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorphonuclear leukocytes
- 2002
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 99:3, s. 1044-1052
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Tidskriftsartikel (refereegranskat)abstract
- 5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of proinflammatory leukotrienes. This study showed that various forms of cell stress, such as chemical stress (sodium arsenite), osmotic stress, or heat shock lead to substantial formation of 5-LO products in freshly isolated human polymorphonuclear leukocytes (PMNLs), when exogenous arachidonic acid (10 μM) was present. In parallel, cell stress led to activation of p38 MAPK (mitogen-activated protein kinase) and mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) kinases, which can phosphorylate 5-LO in vitro. Interestingly, arsenite also caused redistribution of 5-LO from the cytosol to the nuclear membrane. Only minor activation of extracellular signal-regulated kinases and c-jun NH2-terminal kinases was observed, implying that these MAPKs are less important for 5-LO product formation in stress-stimulated PMNLs. Stimulation of 5-LO product formation by Ca++-ionophore A23187 or thapsigargin depended on Ca++; almost no 5-LO product formation was observed in freshly isolated PMNLs when Ca++ was depleted by chelating agents. Also the response toN-formylmethionyl-leucyl-phenylalanine (fMLP) was clearly diminished, but some 5-LO product formation remained. In contrast, stress-induced product formation and translocation of 5-LO, as well as activation of p38 MAPK, occurred also after Ca++ depletion. Moreover, the p38 MAPK inhibitor SB203580 blocked stress-induced 5-LO product formation efficiently, whereas ionophore- or thapsigargin-induced formation of 5-LO products was less sensitive. These data show that cell stress can activate 5-LO in isolated PMNLs by a mechanism that does not involve Ca++ mobilization. This mechanism could function independently of Ca++-mediated 5-LO activation for stimulation of leukotriene biosynthesis under physiologic conditions as well as in inflammatory diseases.
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- Werz, O, et al.
(författare)
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Phorbol ester up-regulates capacities for nuclear translocation and phosphorylation of 5-lipoxygenase in Mono Mac 6 cells and human polymorphonuclear leukocytes
- 2001
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 97:8, s. 2487-2495
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Tidskriftsartikel (refereegranskat)abstract
- The leukotrienes are inflammatory mediators derived from arachidonic acid. It was demonstrated that the priming of leukocytes with phorbol-12-myristate-13-acetate (PMA) leads to the increased formation of 5-lipoxygenase (5-LO) products in parallel with the increased association of 5-LO with the nucleus and the activation of kinases that can phosphorylate 5-LO in vitro. Stimulation of the monocytic cell line Mono Mac 6 with calcium ionophore gave low 5-LO product formation and no detectable redistribution of 5-LO. However, after priming of Mono Mac 6 cells with phorbol esters, ionophore led to the association of 45% to 75% of cellular 5-LO with the nuclear membrane, to 5-LO kinase activation, to enhanced release of arachidonate, and to substantial leukotriene synthesis. Similar results were obtained for human polymorphonuclear leukocytes stimulated with low-dose ionophore. In addition, for each cell type, PMA priming up-regulated leukotriene biosynthesis in the presence of exogenous arachidonic acid. A protein kinase inhibitor, calphostin C, reduced the association of 5-LO with the nucleus and 5-LO kinase activity, and the formation of 5-LO products was inhibited. These results suggest that PMA up-regulates leukotriene biosynthesis not only by increasing the release of endogenous arachidonate, but also by increasing the capacity for 5-LO phosphorylation and for the translocation of 5-LO to the nucleus in leukocytes.
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- BRUNGS, M, et al.
(författare)
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Sequential induction of 5-lipoxygenase gene expression and activity in Mono Mac 6 cells by transforming growth factor beta and 1,25-dihydroxyvitamin D3
- 1995
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 92:1, s. 107-111
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Tidskriftsartikel (refereegranskat)abstract
- 5-Lipoxygenase (5-LO; EC 1.13.11.34) activity in the human monocytic cell line Mono Mac 6 was upregulated by combined treatment with transforming growth factor beta 1 (TGF-beta) and 1,25-dihydroxyvitamin D3 (VD3). In undifferentiated cells, 5-LO enzyme activity was undetectable. After the addition of TGF-beta plus VD3, the activity of intact cells was 800 ng per 10(6) cells--500 times more than the assay detection limit. Also 5-LO protein and mRNA expression were induced > 128-fold and 64-fold, respectively, as compared to undifferentiated cells. Both TGF-beta and VD3 were required for these prominent responses. Either agent alone gave small amounts of 5-LO protein and mRNA but very low 5-LO activities. After the addition of TGF-beta and VD3, the induction of 5-LO protein was obvious after 1 day, but the increase in activity was delayed and did not appear until the second day. Pretreatment of cells with TGF-beta or VD3 alone for 2 days led to 5-LO protein expression but very low enzyme activity. Addition of the lacking second inducer was required for full induction of 5-LO protein expression and for upregulation of enzyme activity. Partial purification of 5-LO from Mono Mac 6 cells and recombination with soluble cellular proteins from different sources indicated the presence of cytosolic factors that affect the activity of 5-LO.
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