Blocking Kv1.3 channels inhibits Th2 lymphocyte function and treats a rat model of asthma

J. Biol. Chem. jbc.M113.517037. First Published on March 18, 2014,doi:10.1074/jbc.M113.517037

1. Shyny Koshy1, 
2. Redwan Huq1, 
3. Mark R. Tanner1, 
4. Mustafa A. Atik1,
5. Paul C. Porter1, 
6. Fatima S. Khan1, 
7. Michael W. Pennington2,
8. Nicola A. Hanania1, 
9. David B. Corry1 and 
10. Christine Beeton1*

+Author Affiliations

1. ¹ Baylor College of Medicine, United States;
2. ² Peptides International, United States

1. ↵* Corresponding author; email: beeton@bcm.edu

Capsule

Background: CCR7- effector memory T lymphocytes are major players in lung inflammation that characterizes allergic asthma.

Results: Blocking Kv1.3 channels reduced the severity of an ovalbumin-induced model of asthma in rats.

Conclusion: Kv1.3 channels are attractive targets for immunomodulation and the treatment of allergic asthma.

Significance: Selective Kv1.3 channel blockers may prove beneficial in the treatment of asthma.

Abstract

Allergic asthma is a chronic inflammatory disease of the airways. Of the different lower airway-infiltrating immune cells that participate in asthma, T lymphocytes that produce Th2 cytokines play important roles in pathogenesis. These T cells are mainly fully-differentiated CCR7- effector memory T (TEM) cells. Targeting TEM cells without affecting CCR7+ naive and central memory (TCM) cells has the potential of treating TEM-mediated diseases, such as asthma, without inducing generalized immunosuppression. The voltage-gated KV1.3 potassium channel is a target for preferential inhibition of TEM cells. Here, we investigated the effects of ShK-186, a selective KV1.3 channel blocker, for the treatment of asthma. A significant proportion of T lymphocytes in the lower airways of subjects with asthma expressed high levels of KV1.3 channels. ShK-186 inhibited the allergen-induced activation of peripheral blood T cells from those subjects. Immunization of F344 rats against ovalbumin, followed by intranasal challenges with ovalbumin, induced airway hyper-reactivity which was reduced by the administration of ShK-186. ShK-186 also reduced total immune infiltrates in the bronchoalveolar lavage and number of infiltrating lymphocytes, eosinophils, and neutrophils assessed by differential counts. Rats with the ovalbumin-induced model of asthma had elevated levels of the Th2 cytokines IL-4, IL-5, and IL-13 measured by ELISA in their bronchoalveolar lavage fluids. ShK-186 administration reduced levels of IL-4 and IL-5 and induced an increase in the production of IL-10. Finally, ShK-186 inhibited the proliferation of lung-infiltrating ovalbumin-specific T cells. Our results suggest that KV1.3 channels represent effective targets for the treatment of allergic asthma.

This Article

1. First Published onMarch 18, 2014, doi:10.1074/jbc.M113.517037jbc.M113.517037.

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