Upregulation of the 5-lipoxygenase pathway in human monocytes by growth and differentiation factors.
5-Lipoxygenase (5-LO) is the key enzyme in leukotriene biosynthesis. Leukotrienes are key mediators of inflammation, allergic and innate immune reactions. 5-LO expression is mainly restricted to a variety of immune competent cells including B-lymphocytes, granulocytes and monocytes/macrophages. Here, we studied the effects of the growth or differentiation factors TGFbeta, 1,25(OH)2D3, GM-CSF and TNFalpha on 5-LO mRNA and protein expression and on 5-LO activity in human monocytes. We found that cultivation of monocytes under standard culture conditions downregulates 5-LO mRNA expression which could be prevented by addition of the four factors. Monocyte 5-LO activity was serum-dependent and cultivation of the cells in serum-free medium strongly downregulated cellular 5-LO activity which could be prevented by TGFbeta, 1,25(OH)2D3, GM-CSF and TNFalpha to different extents. The protein kinase A activator dibutyryl-cAMP blocked the effects of the four factors. The data suggest that 5-LO expression and activity in monocytes is strongly regulated by pro- and anti-inflammatory growth or differentiation factors.
Institute of Pharmaceutical Chemistry/ZAFES, Goethe University, Frankfurt, Germany.
M
M
Wagner
O
O
Werz
D
D
Steinhilber
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation; D055412:Growth Differentiation Factors / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D044967:Serum; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation
D016207:Cytokines; D055412:Growth Differentiation Factors; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D001094:Arachidonate 5-Lipoxygenase