POU2AF1 Functions in the Human Airway Epithelium To Regulate Expression of Host Defense Genes

Abstract

In the process of seeking novel lung host defense regulators by analyzing genome-wide RNA sequence data from normal human airway epithelium, we detected expression of POU2AF1, a known transcription co-factor previously thought to be expressed only in lymphocytes. Lymphocyte contamination of human airway epithelial samples obtained by bronchoscopy and brushing was excluded by immunohistochemistry staining, the observation of up-regulation of POU2AF1 in purified airway basal stem/progenitor cells undergoing differentiation and analysis of differentiating single basal cell clones. Lentivirus-mediated up-regulation of POU2AF1 in airway basal cells induced up-regulation of host defense genes, including MX1, IFIT3, IFITM and known POU2AF1 downstream genes HLA-DRA, ID2, ID3, IL6, BCL6. Interestingly, expression of these genes paralleled changes of POU2AF1 expression during airway epithelium differentiation in vitro, suggesting POU2AF1 helps to maintain a “host defense tone” even in pathogen-free condition. Cigarette smoke, a known risk factor for airway infection, suppressed POU2AF1 expression both in vivo in humans and in vitro in human airway epithelial cultures, accompanied by deregulation of POU2AF1 downstream genes. Finally, enhancing POU2AF1 expression in human airway epithelium attenuated the suppression of host defense genes by smoking. Together, these findings suggest a novel function of POU2AF1 as a potential regulator of host defense genes in the human airway epithelium.

Anti-inflammatory mechanisms of the novel cytokine interleukin-38 in allergic asthma

“…It was notable that IL-38 induced a significant elevation in POU2AF1 gene expression in poly (I:C)/LyoVec-and TNF-α-stimulated cocultures, and the expression of POU2AF1 in airway epithelium was closely related to airway host defense. 37 Moreover, IL-38 upregulated the expression of RGS13, which can inhibit allergic responses in mice by inhibiting IgE receptormediated mast cell degranulation. 38 Consistently, IL-38 has been shown to inhibit the in vitro release of the allergic inflammatory cytokines IL-17 and IL-22 from fungus-activated human PBMCs.…”

Integrated transcriptomic correlation network analysis identifies COPD molecular determinants

“…Among switch genes linked to the NF-κB signaling pathway, we found PRDX4 that is associated with neutrophil activation and degranulation and with I-kappaB phosphorylation that is an important step in the NF-κB activation. Moreover, we found that the gene expression of PRDX4 strongly correlates with the activation of known COPD GWAS interactors SERPINE2, CD79A, and POUF2AF1 [Cha 2009, Groneberg 2004, Mbebi 1999, Ladjemi 2015, Teitell 2003, Zhou 2016, Farner 2016.…”

Reduced CDHR3 expression in children wheezing with rhinovirus

“…Together, these studies show a decreased expression of CDHR3 in wheezing children rather than the expected increase based on the initial study by Bochkov et al 6 The airway epithelium is the first line of defense in the airways. 14 A number of asthma susceptibility genes are expressed in the airway epithelium, [15][16][17] suggesting that processes at the mucosal surface of the airway are critical for the development of asthma. CDHR3 shows a highly relevant expression pattern, with expression in lung (fetal and adult), trachea (adult), ciliated airway epithelial cells in vitro 18 as well as in memory regulatory T cells (CD4 + CD25 + CD45-RA).…”