Journal
MOLECULAR MEDICINE
Volume 21, Issue -, Pages -Publisher
FEINSTEIN INST MED RES
DOI: 10.2119/molmed.2014.00189
Keywords
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Funding
- National Key Basic Research Program of China (973 Program) [2009CB522104]
- National Natural Science Foundation of China [30900576]
- China Postdoctoral Science Foundation [20100480734]
- Yangcheng Scholars Research Program of Guangzhou Municipal Universities [10A024G]
- Program for Tackling Key Problems in Science and Technology of the Local Government in Guangzhou, China
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The host tolerance mechanisms to avian influenza virus (H5N1) infection that limit tissue injury remain unknown. Emerging evidence indicates that cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent Cl-channel, modulates airway inflammation. Janus tyrosine kinase (JAK) 3, a JAK family member that plays a central role in inflammatory responses, prominently contributes to the dysregulated innate immune response upon H5N1 attachment; therefore, this study aims to elucidate whether JAK3 activation induced by H5N1 hemagglutinin (HA) inhibits cAMP-dependent CFTR channels. We performed short-circuit current, immunohistochemistry and molecular analyses of the airway epithelium in Jak3(+/+) and Jak3(+/-) mice. We demonstrate that H5N1 HA attachment inhibits cAMP-dependent CFTR Cl-channels via JAK3-mediated adenylyl cyclase (AC) suppression, which reduces cAMP production. This inhibition leads to increased nuclear factor-kappa B (NF-kappa B) signaling and inflammatory responses. H5N1 HA is detected by TLR4 expressed on respiratory epithelial cells, facilitating JAK3 activation. This activation induces the interaction between TLR4 and G alpha i protein, which blocks ACs. Our findings provide novel insight into the pathogenesis of acute lung injury via the inhibition of cAMP-dependent CFTR channels, indicating that the administration of cAMP-elevating agents and targeting JAK3 may activate host tolerance to infection for the management of influenza virus-induced fatal pneumonia.
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