1. ERK1/2 mitogen-activated protein kinase selectively mediates IL-13-induced lung inflammation and remodeling in vivo.
- Author
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Lee, Patty J., Xuchen Zhang, Peiying Shan, Bing Ma, Chun Geun Lee, Homer, Robert J., Zhou Zhu, Rincon, Mercedes, Mossman, Brooke T., Elias, Jack A., Zhang, Xuchen, Shan, Peiying, Ma, Bing, Lee, Chun Geun, and Zhu, Zhou
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MITOGENS , *PROTEIN kinases , *LUNG diseases , *LABORATORY mice , *PROTEOLYTIC enzymes , *GENETIC mutation , *ANIMAL experimentation , *CARRIER proteins , *CHEMOKINES , *COMPARATIVE studies , *INFLAMMATION , *INTERLEUKINS , *LUNGS , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *RESEARCH , *TRANSFERASES , *EVALUATION research , *MATRIX metalloproteinases - Abstract
IL-13 dysregulation plays a critical role in the pathogenesis of a variety of inflammatory and remodeling diseases. In these settings, STAT6 is believed to be the canonical signaling molecule mediating the tissue effects of IL-13. Signaling cascades involving MAPKs have been linked to inflammation and remodeling. We hypothesized that MAPKs play critical roles in effector responses induced by IL-13 in the lung. We found that Tg IL-13 expression in the lung led to potent activation of ERK1/2 but not JNK1/2 or p38. ERK1/2 activation also occurred in mice with null mutations of STAT6. Systemic administration of the MAPK/ERK kinase 1 (MEK1) inhibitor PD98059 or use of Tg mice in which a dominant-negative MEK1 construct was expressed inhibited IL-13-induced inflammation and alveolar remodeling. There were associated decreases in IL-13-induced chemokines (MIP-1alpha/CCL-3, MIP-1beta/CCL-4, MIP-2/CXCL-1, RANTES/CCL-5), MMP-2, -9, -12, and -14, and cathepsin B and increased levels of alpha1-antitrypsin. IL-13-induced tissue and molecular responses were noted that were equally and differentially dependent on ERK1/2 and STAT6 signaling. Thus, ERK1/2 is activated by IL-13 in the lung in a STAT6-independent manner where it contributes to IL-13-induced inflammation and remodeling and is required for optimal IL-13 stimulation of specific chemokines and proteases as well as the inhibition of specific antiproteases. ERK1/2 regulators may be useful in the treatment of IL-13-induced diseases and disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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