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ERK1/2 mitogen-activated protein kinase selectively mediates IL-13-induced lung inflammation and remodeling in vivo

Patty J Lee1, Xuchen Zhang, Peiying Shan

  • 1Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.

The Journal of Clinical Investigation
|December 24, 2005
PubMed

Insights

Interleukin-13 (IL-13) triggers lung inflammation and remodeling partly via ERK1/2, a pathway independent of STAT6. Targeting ERK1/2 may treat IL-13-driven diseases.

Area of Science:

  • Immunology
  • Cell Biology
  • Pulmonology

Background:

  • Interleukin-13 (IL-13) dysregulation is central to inflammatory and remodeling diseases.
  • Signal transducer and activator of transcription 6 (STAT6) is considered the primary mediator of IL-13 effects.
  • Mitogen-activated protein kinases (MAPKs) are implicated in inflammation and tissue remodeling.

Purpose of the Study:

  • To investigate the role of MAPKs in IL-13-induced effector responses in the lung.
  • To determine the relationship between IL-13, STAT6, and MAPK signaling pathways in lung inflammation and remodeling.

Main Methods:

  • Transgenic (Tg) IL-13 expression in mouse lungs.
  • Analysis of MAPK activation (ERK1/2, JNK1/2, p38) in response to IL-13.
  • Assessment of IL-13-induced inflammation and alveolar remodeling using MEK1 inhibitors (PD98059) and dominant-negative MEK1 constructs.
  • Quantification of chemokines, matrix metalloproteinases (MMPs), cathepsin B, and alpha1-antitrypsin levels.

Main Results:

  • IL-13 induced significant ERK1/2 activation in the lung, independent of STAT6.
  • Inhibition of ERK1/2 signaling reduced IL-13-induced inflammation, alveolar remodeling, and altered levels of specific chemokines, MMPs, cathepsin B, and alpha1-antitrypsin.
  • Both ERK1/2 and STAT6 signaling pathways contribute to IL-13-mediated responses in a partially overlapping and partially distinct manner.

Conclusions:

  • Extracellular signal-regulated kinase 1/2 (ERK1/2) is activated by IL-13 in the lung independently of STAT6.
  • ERK1/2 signaling contributes significantly to IL-13-induced lung inflammation and remodeling.
  • Regulators of ERK1/2 may represent novel therapeutic targets for IL-13-mediated inflammatory and remodeling diseases.

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