title: Leukotriene D(4) induces gene expression in human monocytes through cysteinyl leukotriene type I receptor.
abstract: 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.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Woszczek
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Chen
authors.forename: Sahrudaya
authors.initials: S
authors.lastname: Nagineni
authors.forename: Steven
authors.initials: S
authors.lastname: Kern
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barb
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Munson
authors.forename: Carolea
authors.initials: C
authors.lastname: Logun
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
authors.forename: James H
authors.initials: JH
authors.lastname: Shelhamer
mesh_terms: 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
chemical_list: D008565:Membrane Proteins; D011506:Proteins; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C083169:leukotriene D4 receptor; D002118:Calcium