DNA-dependent protein kinase plays a role in inflammation independent of DNA-damage repair function and its inhibition blocks allergic inflammation in mice and modulates human CD4+ T cell function without causing SCID (HYP7P.264)

Abstract

Abstract 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 including VCAM-1. Here we show that DNA-PK protein level and function are critical for VCAM-1 expression in TNF-α-treated human endothelial and mouse lung smooth muscle cells and are required for monocytes adhesion. Interestingly, DNA-PK activation and subsequent VCAM-1 expression in presence of TNF occurred independently of DNA breaks/repair. Administration of the DNA-PK inhibitor, NU7441, and DNA-PK heterozygosity reduced airway eosinophilia, mucus hypersecretion, airway hyperresponsiveness (AHR), and OVA-specific IgE production in asthma model of mice. Such effects correlated with a marked reduction in lung VCAM-1 expression and production of several inflammatory cytokines. Remarkably, such protection occurred without causing SCID. These results were confirmed in a chronic model of asthma using house dust mite. DNA-PK inhibition reduced Th2 cytokines production without affecting Th1 cytokines production and cell proliferation in CD3/CD28-stimulated human CD4+T cells potentially by blocking gata-3 expression. In mouse CD4+T cells, DNA-PK inhibition, in vitro, severely blocked CD3/CD28-induced gata-3 and t-bet expression and prevented differentiation of Th1 and Th2 cells. Thus, our results suggest DNA-PK as a novel determinant of asthma and a potential target for the treatment of the disease.