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DNA‐Dependent Protein Kinase Inhibition Blocks Asthma in Mice and Modulates Human Endothelial and CD4 + T Cell Function Without Causing SCID
Author(s) -
Pyakurel Kusma,
Ghonim Mohamed,
Ju Jihang,
Rodriguez Paulo,
Lammi Matthew,
Davis Christian,
Abughazleh Mohammad,
Naura Amarjit,
Boulares Hamid
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.626.6
Subject(s) - microbiology and biotechnology , immunology , ovalbumin , eosinophil , allergic inflammation , biology , chemistry , inflammation , immune system , asthma
We reported that DNA‐dependent Protein Kinase (DNA‐PK) is critical for the expression of NF‐κB‐dependent genes in TNF‐α‐treated glioblastoma cells, suggesting an involvement in inflammation. Cell culture and ovalbumin (OVA) or house dust mite (HDM)‐based murine asthma models were used in this study. Results DNA‐PK was essential for monocyte adhesion to TNF‐α–treated‐endothelial cells. Administration of the DNA‐PK inhibitor, NU7441, reduced airway eosinophilia, mucus hypersecretion, airway hyperresponsiveness (AHR), and OVA‐specific IgE production in mice. Such effects correlated with a marked reduction in lung VCAM‐1 expression and production of several inflammatory cytokines and chemokines. DNA‐PK heterozygosity also prevented manifestation of asthma‐like traits. Remarkably, such protection occurred without causing SCID. These results were confirmed in a chronic model of asthma using HDM. Adoptive transfer of Th2‐skewed OT‐II‐WT CD4 + T cells reversed IgE and Th2 cytokine production but not AHR in ova‐challenged DNA‐PKcs +/‐ mice. DNA‐PK inhibition reduced IL‐4/IL‐5/IL‐13/eotaxin/IL‐8/MCP‐1 production without affecting IL‐2/IL‐12/IFN‐γ/IP‐10 production in CD3/CD28‐stimulated human T cells potentially by blocking expression of gata‐3 . These effects occurred without significant reductions in T‐cell proliferation. In mouse T cells, DNA‐PK inhibition, in vitro , severely blocked CD3/CD28‐induced gata‐3 and t‐bet expression in T cells and prevented differentiation of Th1 and Th2 cells. Our results suggest DNA‐PK as a novel determinant of asthma and a potential target for the treatment of the disease.
Support: NIH; AHA; LCRC