Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 181, Issue 12, Pages 1310-1317Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.200907-1166oc
Keywords
Th2 cells; voltage-dependent calcium channels; allergic asthma; antisense oligonucleotides
Categories
Funding
- Agence Nationale de la Recherche [ANR-07-BLAN-0102]
- Ligue Contre le Cancer
- association 111 des Arts
- Conseil Regional de Midi-Pyrenees
- Agence Nationale de la Recherche (ANR) [ANR-07-BLAN-0102] Funding Source: Agence Nationale de la Recherche (ANR)
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Rationale: Th2 cells orchestrate allergic asthma and the cytokines they produce (IL-4, IL-5, and IL-13) are deleterious in allergy. Therefore, it is important to identify key signaling molecules expressed by Th2 cells that are essential for their function. We have previously shown that dihydropyridines selectively modulate Th2 cell functions. Objectives: Because dihydropyridines bind to and modulate voltage-dependent calcium (Ca(v)1) channel in excitable cells, we aimed at showing that Th2 cells selectively express functional Ca(v)1-related channels, the inhibition of which may prevent asthma. Methods: We looked for Ca(v)1 channel expression in Th2 and Th1 cells by real-time polymerase chain reaction and Western blotting. We sequenced the isoforms expressed by Th2 cells and tested whether antisense oligodeoxynucleotides (Ca(v)1AS) affected Ca2+ signaling and cytokine production. Finally, we tested the effect of Ca(v)1AS in the passive asthma model by injection of ovalbumin-specific Th2 cells transfected with Ca(v)1AS into BALB/c mice challenged with intranasal ovalbumin and in the active model of asthma by intranasal delivery of Ca(v)1AS together with soluble ovalbumin in BALB/c mice previously immunized with ovalbumin in alum. Measurements and Main Results: We show that mouse Th2 but not Th1 cells expressed Ca(v)1.2 and Ca(v)1.3 channels. Th2 cells transfected with Ca(v)1AS had impaired Ca2+ signaling and cytokine production, and lost their ability to induce airway inflammation on adoptive transfer. Furthermore, intranasal administration of Ca(v)1AS suppressed airway inflammation and hyperreactivity in an active model of asthma. Conclusions: These results indicate that Th2 cells selectively express Ca(v)1 channels that may be efficiently targeted in T lymphocytes to prevent experimental asthma.
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