title: Parthenolide inhibits ERK and AP-1 which are dysregulated and contribute to excessive IL-8 expression and secretion in cystic fibrosis cells.
abstract: BACKGROUND
  Excessive secretion of IL-8 characterizes cystic fibrosis (CF). This has been attributed to excessive activation of epithelial cell I-κB Kinase and/or NFκB. Maximum IL-8 production requires 3 cooperative mechanisms: 1) release of the promoter from repression; 2) activation of transcription by NFκB and AP-1; 3) stabilization of mRNA by p38-MAPK. Little is known about regulation of IL-8 by MAPKs or AP-1 in CF.
  
  
  METHODS
  We studied our hypothesis in vitro using 3-cellular models. Two of these models are transformed cell lines with defective versus normal cystic fibrosis transmembrane conductance regulator (CFTR) expression: an antisense/sense transfected cell line and the patient derived IB3-1/S9. In the third series of studies, we studied primary necropsy human tracheal epithelial cells treated with an inhibitor of CFTR function. All cell lines were pretreated with parthenolide and then stimulated with TNFα and/or IL-1β.
  
  
  RESULTS
  In response to stimulation with TNFα and/or IL-1β, IL-8 production and mRNA expression was greater in CF-type cells than in non-CF controls. This was associated with enhanced phosphorylation of p38, ERK1/2 and JNK and increased activation of AP-1. Since we previously showed that parthenolide inhibits excessive IL-8 production by CF cells, we evaluated its effects on MAPK and AP-1 activation and showed that parthenolide inhibited ERK and AP-1 activation. Using a luciferase promoter assay, our studies showed that parthenolide decreased activation of the IL-8 promoter in CF cells stimulated with TNFα/IL-1β.
  
  
  CONCLUSIONS
  In addition to NFκB MAPKs ERK, JNK and p38 and the transcription factor AP-1 are also dysregulated in CF epithelial cells. Parthenolide inhibited both NFκB and MAPK/AP-1 pathways contributing to the inhibition of IL-8 production.
authors: Department of Pediatrics, Case Western Reserve University, 11100 Euclid Avenue, BRB-822 Cleveland Ohio 44106, OH 44106, USA.
authors: Aicha
authors: A
authors: Saadane
authors: Department of Pediatrics, Case Western Reserve University, 11100 Euclid Avenue, BRB-822 Cleveland Ohio 44106, OH 44106, USA.
authors: Jean
authors: J
authors: Eastman
authors: Department of Pediatrics, Case Western Reserve University, 11100 Euclid Avenue, BRB-822 Cleveland Ohio 44106, OH 44106, USA.
authors: Melvin
authors: M
authors: Berger
authors: Department of Pediatrics, Case Western Reserve University, 11100 Euclid Avenue, BRB-822 Cleveland Ohio 44106, OH 44106, USA.
authors: Tracey L
authors: TL
authors: Bonfield