Regulation of human airway epithelial cell IL-8 expression by MAP kinases

Am J Physiol Lung Cell Mol Physiol. 2002 Oct;283(4):L690-9. doi: 10.1152/ajplung.00060.2002.


Recent studies indicate that maximal IL-8 protein expression requires activation of NF-kappaB as well as activation of the MAP kinases ERK, JNK, and p38. However, the precise relationship between NF-kappaB transactivation and MAP kinase activation remains unclear. We examined the requirements of NF-kappaB, ERK, JNK, and p38 for TNF-alpha-induced transcription from the IL-8 promoter in a human bronchial epithelial cell line. Treatment with TNF-alpha induced activation of all three MAP kinases. Using a combination of chemical and dominant-negative inhibitors, we found that inhibition of NF-kappaB, ERK, and JNK, but not p38, each decreased TNF-alpha-induced transcription from the IL-8 promoter. Inhibition of JNK signaling also substantially reduced TNF-alpha-induced NF-kappaB transactivation, whereas inhibition of ERK and p38 had no effect. On the other hand, ERK was required and sufficient for TNF-alpha-induced activation of activator protein (AP)-1 promoter sequences, which together function as a basal level enhancer. JNK activation was also required for AP-1 transactivation. Finally, inhibition of p38 attenuated IL-8 protein abundance, suggesting that p38 regulates IL-8 expression in a posttranscriptional manner. We conclude that, in human airway epithelial cells, MAP kinases may regulate IL-8 promoter activity by NF-kappaB-dependent (in the case of JNK) and -independent (ERK) processes, as well as by posttranscriptional mechanisms (p38).

Publication types

  • Editorial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkaloids / metabolism
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Gene Expression / immunology
  • Humans
  • Interleukin-8 / genetics*
  • Interleukin-8 / metabolism*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / immunology*
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases / metabolism
  • Promoter Regions, Genetic / immunology
  • Respiratory Mucosa / cytology*
  • Respiratory Mucosa / enzymology*
  • Respiratory Mucosa / immunology
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic / physiology
  • Tumor Necrosis Factor-alpha / pharmacology
  • p38 Mitogen-Activated Protein Kinases


  • Alkaloids
  • Antineoplastic Agents
  • Interleukin-8
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • neojiangyouaconitine
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases