5-Lipoxygenase upregulation by dexamethasone in human mast cells.
In spite of intensive research, our understanding of the regulation of expression of 5-LO (the key enzyme in the leukotriene metabolism) remains fragmentary. We investigated the effects of dexamethasone on the expression of this gene in a binary model consisting of two clones of the human mast cell line HMC-1, one with a 5-LO-negative and the other with a 5-LO-positive phenotype, respectively. When dexamethasone was included in the culture medium at a physiologically relevant concentration, biosynthesis of 5-LO derivatives increased considerably not only in the 5-LO-negative HMC-1 cells (approx 10-fold) but also in the 5-LO-positive cells, characterized by an already substantial enzyme activity. Consistently, Northern blot analysis revealed that a dramatic increase in the abundance of 5-LO mRNA occurred when the cells were exposed to dexamethasone. Likewise, a significant increase in the immunoreactive 5-LO protein was detected by Western blotting. In contrast, dexamethasone seemed to have no effect on the expression of two other genes of pivotal importance in leukotriene biosynthesis, viz. FLAP and LTC(4) synthase. We conclude that in human mast cells glucocorticoids effectively and selectively upregulate the expression of 5-LO.
Colamorea
T
T
Department of Clinical Immunology and Allergology, University of Bari, Bari, 70124, Italy.
Di Paola
R
R
Macchia
F
F
Guerrese
M C
MC
Tursi
A
A
Butterfield
J H
JH
Caiaffa
M F
MF
Haeggström
J Z
JZ
Macchia
L
L
D058927:5-Lipoxygenase-Activating Proteins; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D002999:Clone Cells; D003907:Dexamethasone / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D015289:Leukotrienes / Q000096:biosynthesis; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology*; D008565:Membrane Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D005938:Glucocorticoids; D015289:Leukotrienes; D008565:Membrane Proteins; D012333:RNA, Messenger; D003907:Dexamethasone; D001094:Arachidonate 5-Lipoxygenase; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase