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Glycogen Synthase Kinase-3 Inhibition Attenuates Asthma in Mice

¹ Department of Pharmacology, Yong Loo Lin School of Medicine, Singapore; ² Center for Translational Medicine and Therapeutics, William Harvey Research Institute, London, United Kingdom; ³ Department of Physiology, Yong Loo Lin School of Medicine, Singapore; and ⁴ Immunology Program, Office of Life Sciences, National University of Singapore, Singapore

Correspondence and requests for reprints should be addressed to W. S. Fred Wong, Ph.D., Immunology Program, Office of Life Sciences, National University of Singapore, 28 Medical Drive, #03-05, Singapore 117456. E-mail: phcwongf{at}nus.edu.sg

Rationale: Persistent activation of nuclear factor-B has been associated with the development of asthma. Glycogen synthase kinase-3 is known to regulate the activity of nuclear factor-B.

Objectives: We hypothesized that inhibition of glycogen synthase kinase-3 may have anti-inflammatory effects in allergic asthma.

Methods: BALB/c mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and for cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and for the expression of inflammatory biomarkers. Serum immunoglobulin E levels were determined by enzyme-linked immunosorbant assay. Airway hyperresponsiveness was monitored by direct airway resistance analysis.

Measurements and Main Results: Intravenous administration of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a selective glycogen synthase kinase-3 inhibitor, significantly inhibited ovalbumin-induced increases in total cell counts, eosinophil counts, and IL-5, IL-13, and eotaxin levels recovered in bronchoalveolar lavage fluid in a dose-dependent manner. TDZD-8 substantially reduced the serum levels of ovalbumin-specific IgE. Histologic studies showed that TDZD-8 dramatically inhibited ovalbumin-induced lung tissue eosinophilia and airway mucus production. TDZD-8 also markedly suppressed ovalbumin-induced mRNA expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, Muc5ac, and three members of the chitinase family (acidic mammalian chitinase, Ym1, and Ym2). In addition, TDZD-8 significantly reduced ovalbumin-induced airway hyperresponsiveness to inhaled methacholine. Western blot analysis of whole lung lysates revealed that TDZD-8 markedly attenuated the phosphorylation of the nuclear factor-B subunit p65 from ovalbumin-challenged mice.

Conclusions: Our findings suggest that inhibition of glycogen synthase kinase-3 may provide a novel means for the treatment of allergic airway inflammation.

Key Words: bronchoalveolar lavage fluid • ovalbumin • nuclear factor-B • eosinophilia • mucus hypersecretion

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Persistent activation of nuclear factor (NF)-B is associated with asthma. Glycogen synthase kinase-3 (GSK-3) is known to regulate NF-B activity. What This Study Adds to the Field In this study, inhibition of GSK-3 reduced the severity of ovalbumin-induced allergic asthma.

 

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