Steroid Insensitivity in Asthma Linked to Defect of PP2A Enzyme, May Provide Key to New Treatments

Corticosteroid insensitivity is a barrier of treatment of severe asthma, but the molecular mechanism of the insensitivity has not been elucidated. This UK study investigated the role of protein phosphate 2A (PP2A), a serine/threonine phosphatase.

Steroid sensitivity was determined by the dexamethasone ability to inhibit TNF-alpha-induced IL-8 or LPS-induced TNF-alpha production. The receptor expression and nuclear translocation were analysed by Western-blotting.

Interleukin-8, a chemokine of the CXC subfamily. CXCL8 (IL-8) forms a chemotactic gradient that directs leukocytes (mostly PMNs) towards site of tissue injury/infection. Image source: Wikipedia, public domain.

A PP2A inhibitor reduced steroid sensitivity with reduced glucocorticoid receptor nuclear translocation and increased phosphorylation. PP2A knockdown by RNA interference showed similar effects. In peripheral blood mononuclear cells from severe asthma, the PP2A expression was reduced. Conversely, PP2A overexpression increased steroid sensitivity.

The authors concluded that PP2A regulates glucocorticoid receptor nuclear translocation and corticosteroid sensitivity. This newly-discovered mechanism may provide insight for development of new therapy for severe asthma.

52 chemokines from 4 families have been described. They interact with 20 receptors (click here for a larger image):


Defects of Protein Phosphatase 2A Causes Corticosteroid Insensitivity in Severe Asthma. Kobayashi Y, Mercado N, Barnes PJ, Ito K. PLoS One. 2011;6(12):e27627. Epub 2011 Dec 19.


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