title: Tissue factor inflammatory response regulated by promoter genotype and p38 MAPK in neonatal vs. adult microvascular endothelial cells.
abstract: OBJECTIVE
  Variable tissue factor (TF) expression by human microvascular endothelial cells (HMVEC) may be regulated by two promoter haplotypes, distinguished by an 18-basepair deletion (D) or insertion (I) at -1,208. We sought to determine the relationship between these haplotypes and interleukin-1α (IL-1α)-induced TF expression in neonatal versus adult HMVEC.
  
  
  RESULTS
  IL-1-stimulated TF mRNA, protein, and activity were significantly higher in neonatal compared to adult D/D donors. IL-1-stimulated HMVEC from neonatal D/D donors expressed threefold higher levels of TF mRNA, twofold higher TF protein, and fourfold increased TF activity compared to HMVEC from adult D/D donors. These results indicate that homozygosity for the D haplotype is characterized by increased response to IL-1 in neonates, but not adults. IL-1 induced increased phosphorylation of p38 mitogen-activated protein kinase (MAPK), which was significantly greater in neonatal compared to adult HMVEC. Moreover, inhibition of the p38 MAPK pathway reduced IL-1-stimulated TF mRNA expression in D/D neonatal but not adult HMVEC.
  
  
  CONCLUSIONS
  Upregulation of D/D neonatal HMVEC TF expression by IL-1 is mediated through the p38 MAPK pathway. This heightened response of D/D neonatal HMVEC to inflammatory stimuli may contribute to increased microvascular coagulopathies in susceptible newborn infants.
authors.affiliation: Hematology Research Laboratory, 510 Research Institute, CHOC Children's Hospital of Orange County, 1201 W. La Veta Avenue, Orange, CA, 92868, USA, jbuzby@choc.org.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Buzby
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Williams
authors.forename: Karen L
authors.initials: KL
authors.lastname: Imfeld
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kunicki
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Nugent
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D053582:Interleukin-1alpha / Q000494:pharmacology; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D053582:Interleukin-1alpha; D012333:RNA, Messenger; D013925:Thromboplastin; D048051:p38 Mitogen-Activated Protein Kinases