title: The up-regulation of monocyte chemoattractant protein-1 (MCP-1) in Ea.hy 926 endothelial cells under long-term low folate stress is mediated by the p38 MAPK pathway.
abstract: OBJECTIVE
  Monocyte chemoattractant protein-1 (MCP-1), encoded by the CCL2 gene, plays an important role in the initiation and progression of atherosclerosis. Ea.hy 926 endothelial cells grown under low folate conditions (LO cells) synthesize more MCP-1 mRNA and secrete more MCP-1 protein than folate-replete control cells (HI cells). We investigated the mechanisms underlying the modulation of MCP-1 expression by long-term "folate stress".
  
  
  RESULTS
  CCL2 transcription, assessed using promoter-reporter assays, is up-regulated in LO cells relative to HI cells, whereas MCP-1 mRNA stability is unchanged. This quantitative transcriptional bias under chronic low folate conditions is not attributable to differences in active NF-kappaB, but is associated with elevated levels of both total p38 and phospho-p38 that are detectable by Western immunoblotting. Transient, acute methotrexate-mediated folate depletion or exposure to high concentrations of homocysteine (Hcy) had no effect on MCP-1 synthesis by Ea.hy 926 cells. The p38 inhibitor SB-203580 abolished the excess MCP-1 production by LO cells. The quantitative transcriptional bias of CCL2 in LO cells was retained following massive induction by TNF-alpha.
  
  
  CONCLUSIONS
  During long-term folate stress, p38 is the primary determinant of CCL2 transcription. Long-term folate insufficiency "primes" Ea.hy 926 endothelial cells to have a quantitatively more vigorous response to cytokine-mediated inflammatory stress.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Lu
authors.forename: Liselotte E
authors.initials: LE
authors.lastname: Jensen
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Huang
authors.forename: Carmel
authors.initials: C
authors.lastname: Kealey
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Whitehead
mesh_terms: D050197:Atherosclerosis / Q000378:metabolism*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005492:Folic Acid / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D008727:Methotrexate / Q000494:pharmacology; D008954:Models, Biological; D014158:Transcription, Genetic; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005492:Folic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D008727:Methotrexate