Leukotriene D(4) induces gene expression in human monocytes through cysteinyl leukotriene type I receptor.
BACKGROUND
Cysteinyl leukotrienes (CysLTs) are important mediators of innate immune responsiveness and chronic inflammatory diseases. CysLTs acting through CysLT receptors can influence the migration and activity of cells, such as eosinophils, monocytes, and dendritic cells.


OBJECTIVE
We sought to determine the gene expression signature of human monocytes in response to CysLTs and to elucidate the signaling pathways involved in monocyte activation.


METHODS
Gene expression was analyzed by using oligonucleotide microarrays. Responsiveness to CysLTs was assessed by using real-time PCR, calcium flux, kinase activation, and chemotaxis assays.


RESULTS
CysLT type 1 receptor (CysLTR(1)) transcript 1 is predominantly expressed in human monocytes, and CysLTs signal through CysLTR(1) in these cells. Several immediate-early genes, including early growth response 2 and 3, FBJ murine osteosarcoma viral oncogene homolog B, activating transcription factor 3, and nuclear receptor subfamily 4 were significantly induced by leukotriene (LT) D(4). This effect was mediated by CysLTR(1) coupled to the G protein alpha inhibitory subunit, activation of phospholipase C, and inositol-1,4,5-triphosphate and store-operated calcium channels. LTD(4) induced p38 mitogen-activated protein kinase phosphorylation, a pathway also involved in the regulation of immediate-early gene expression in monocytes. LTD(4) stimulated monocyte chemotactic activity that was fully blocked by a selective CysLTR(1) inhibitor, MK571, and pertussis toxin, suggesting that CysLTR(1) coupled to the G protein alpha inhibitory subunit is a dominant functional pathway in human monocytes.


CONCLUSIONS
Our data show that CysLTs acting through CysLTR(1) can significantly influence the activation and migration of human monocytes and that these effects can be fully inhibited by CysLTR(1) antagonists.
Woszczek
Grzegorz
G
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Chen
Li-Yuan
LY
Nagineni
Sahrudaya
S
Kern
Steven
S
Barb
Jennifer
J
Munson
Peter J
PJ
Logun
Carolea
C
Danner
Robert L
RL
Shelhamer
James H
JH
D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D017998:Leukotriene D4 / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D008565:Membrane Proteins; D011506:Proteins; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C083169:leukotriene D4 receptor; D002118:Calcium