Induction of granulocyte-macrophage colony-stimulating factor by a new cytokine, ML-1 (IL-17F), via Raf I-MEK-ERK pathway

Mio Kawaguchi, Fumio Kokubu, Miho Odaka, Shin Watanabe, Shintaro Suzuki, Koushi Ieki, Satoshi Matsukura, Masatsugu Kurokawa, Mitsuru Adachi, Shau Ku Huang

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Background ML-1 (IL-17F) is a recently discovered cytokine, and its function remains elusive. GM-CSF is a crucial cytokine for the maturation of various cell types and regulates allergic airway inflammation. Objective The functional effect of ML-1 in the expression of GM-CSF was investigated. Methods The levels of gene and protein expression in normal human bronchial epithelial cells (NHBEs) in the presence or absence of various kinase inhibitors or, in some cases, of a Raf1 dominant-negative mutant were determined by RT-PCR and ELISA, respectively. Western blotting was performed to investigate kinase activation. Results The results showed first that ML-1 induces, in a time-dependent and dose-dependent manner, the gene and protein expression for GM-CSF NHBEs, which are associated with activation of Raf1 and MAP kinase kinase (MEK) kinases. Selective MEK inhibitors, PD98059 and U0126, and Raf1 kinase inhibitor I significantly inhibited ML-1-induced GM-CSF production. Furthermore, overexpression of Raf1 dominant-negative mutants inhibited IL-17F-induced GMCSF expression. The combination of PD98059 and Raf1 kinase inhibitor I completely blocked GM-CSF production, whereas 2 protein kinase C inhibitors, Ro-31-7549 and GF109203X, and a phosphatidylinositol 3-kinase inhibitor, LY294002, showed no inhibitory effect. Conclusion These findings suggest that ML-1 induces GM-CSF expression through the activation of the Raf1-MEK-extracellular signal-regulated kinase 1/2 pathway.

Original languageEnglish
Pages (from-to)444-450
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume114
Issue number2
DOIs
Publication statusPublished - Aug 1 2004
Externally publishedYes

Keywords

  • Bronchial epithelial cells
  • Dimethyl sulfoxide
  • DMSO
  • ERK
  • ERK1/2
  • Extracellular signal-regulated kinase
  • GM-CSF
  • MAP kinase
  • MAP kinase kinase
  • MEK
  • NF-κB
  • NHBE
  • Normal human bronchial epithelial cell
  • Nuclear factor κB
  • PI3K
  • Raf1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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