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Src mediates cytokine-stimulated gene expression in airway myocytes through ERK MAPK

Cherie A Singer1, Beata Lontay, Helmut Unruh

  • 1University of Nevada School of Medicine, Department of Pharmacology Reno, NV 89557, USA. csinger@medicine.nevada.edu.

Cell Communication and Signaling : CCS
|May 24, 2011
PubMed

Insights

Src tyrosine kinases regulate inflammatory gene expression in airway smooth muscle cells by activating extracellular signal-regulated kinases (ERK) mitogen-activated protein kinases (MAPK). This study identifies Src as a key upstream mediator in cytokine-induced inflammation.

Area of Science:

  • Cellular and Molecular Biology
  • Immunology
  • Respiratory Medicine

Background:

  • Mitogen-activated protein kinases (MAPK), including p38 and extracellular signal-regulated kinases (ERK), are crucial in inflammatory gene expression within airway smooth muscle cells.
  • Cytokine signaling pathways in airway inflammation are complex and involve multiple kinase cascades.

Purpose of the Study:

  • To investigate the role of Src tyrosine kinases as upstream signaling intermediaries in cytokine-induced MAPK activation and inflammatory gene expression in human airway myocytes.
  • To elucidate the specific MAPK pathways and transcription factors regulated by Src in response to inflammatory cytokines.

Main Methods:

  • Human airway myocytes were treated with inflammatory cytokines (IL-1β, TNFα, IFNγ).
  • Src family tyrosine kinase activity was measured using immune-complex assays.
  • The effect of PP1, a specific Src inhibitor, on cytokine-stimulated gene expression (IL-1β, IL-6, IL-8) and MAPK phosphorylation (ERK, p38) was assessed.
  • STAT1 and STAT3 phosphorylation was also evaluated in the presence of PP1.

Main Results:

  • Cytokine stimulation rapidly increased Src family tyrosine kinase activity.
  • Inhibition of Src with PP1 blocked the expression of IL-1β, IL-6, and IL-8.
  • PP1 treatment reduced ERK phosphorylation but did not affect p38 MAPK phosphorylation.
  • Src inhibition did not alter cytokine-induced STAT1 or STAT3 phosphorylation.

Conclusions:

  • Src tyrosine kinases are essential signaling intermediaries in the regulation of IL-1β, IL-6, and IL-8 expression in airway smooth muscle cells.
  • Src-mediated inflammatory gene expression is dependent on the activation of ERK MAPK, not p38 MAPK or STAT1/STAT3.
  • These findings highlight Src as a potential therapeutic target for inflammatory airway diseases.

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