IL-1beta induces IL-8 in bronchial cells via NF-kappaB and NF-IL6 transcription factors and can be suppressed by glucocorticoids

Pulm Pharmacol Ther. 2005;18(5):337-45. doi: 10.1016/j.pupt.2004.12.015. Epub 2005 Mar 17.

Abstract

IL-1beta may contribute to airway inflammation by inducing pro-inflammatory cytokines and chemokines from bronchial epithelial cells. In the current study, we investigated the cis-acting sites within the IL-8 promoter, and signalling pathways important in IL-8 production from BEAS2B cells following IL-1beta stimulation. IL-1beta treatment (0.1-10 ng/mL) upregulated IL-8 protein production in a dose dependent manner and IL-8 mRNA in a time dependent manner. IL-1beta induced upregulation of IL-8 promoter-reporter constructs, indicating that the mechanism of upregulation was pre-transcriptional. Using IL-8 promoter constructs with mutated cis-acting sites, it was found that both the NF-kappaB and NF-IL6 sites together were required for IL-8 promoter induction following IL-1beta treatment. Using chemical inhibitors or dominant negative mutants, we found that IL-8 promoter activity required IkappaB kinase beta, IkappaB, but not the MAP kinases p38 or c-Jun N-terminal kinase 2. Fluticasone propionate was able to suppress IL-1beta induced IL-8 protein and promoter activation, using both a -1481 bp fragment and a -133 bp fragment, indicating that the glucocorticoid response element found at -330 bp was not required for fluticasone mediated suppression of IL-8 promoter activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / therapeutic use
  • Anti-Inflammatory Agents / therapeutic use
  • Asthma / drug therapy
  • Asthma / pathology
  • Bronchi / cytology
  • Bronchi / drug effects*
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Fluticasone
  • Humans
  • Interleukin-1 / administration & dosage
  • Interleukin-1 / pharmacology*
  • Interleukin-8 / metabolism*
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Transcription Factors
  • Up-Regulation

Substances

  • Androstadienes
  • Anti-Inflammatory Agents
  • CCAAT-Enhancer-Binding Protein-beta
  • Interleukin-1
  • Interleukin-8
  • NF-kappa B
  • RNA, Messenger
  • Transcription Factors
  • Fluticasone