Interleukin-13 Inhibits Lipopolysaccharide-Induced BPIFA1 Expression in Nasal Epithelial Cells

Abstract

Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is expressed in human nasopharyngeal and respiratory epithelium and has demonstrated antimicrobial activity. SPLUNC1 is now referred to as bactericidal/permeability-increasing fold containing family A, member 1 (BPIFA1). Reduced BPIFA1 expression is associated with bacterial colonization in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Interleukin 13 (IL-13), predominately secreted by T helper 2 (TH2) cells, has been found to contribute to airway allergies and suppress BPIFA1 expression in nasal epithelial cells. However, the molecular mechanism of IL-13 perturbation of bacterial infection and BPIFA1 expression in host airways remains unclear. In this study, we found that lipopolysaccharide (LPS)-induced BPIFA1 expression in nasal epithelial cells was mediated through the JNK/c-Jun signaling pathway and AP-1 activation. We further demonstrated that IL-13 downregulated the LPS-induced activation of phosphorylated JNK and c-Jun, followed by attenuation of BPIFA1 expression. Moreover, the immunohistochemical analysis showed that IL-13 prominently suppressed BPIFA1 expression in eosinophilic CRSwNP patients with bacterial infection. Taken together, these results suggest that IL-13 plays a critical role in attenuation of bacteria-induced BPIFA1 expression that may result in eosinophilic CRSwNP.

The Role of BPIFA1 in Upper Airway Microbial Infections and Correlated Diseases

“…How these studies were executed and their materials and methods are shown in Table 2 [ 9 , 11 – 13 , 15 , 17 – 19 , 39 ]. Furthermore, Table 3 summarizes the working mechanisms utilized by BPIFA1 to protect humans from related pathogens, viral or bacterial, that infect the upper airway.…”

“…Patients with CRSwNP had higher secretion of interleukin-13 (IL-13), which appears to play a critical role in downregulating BPIFA1 expression. In nasal epithelial cells, IL-13 attenuates BPIFA1 expression by downregulating the lipopolysaccharide- (LPS-) induced activation of phosphorylated JNK and c-Jun [ 39 ].…”

“…It was shown that, in defending the lower airway against Mycoplasma pneumonia infection, BPIFA1 signaled through the TLR2-NF- κ B pathway and also through TLR2-induced (MARK)/activating protein 1 (AP-1) in human lung epithelium cells [ 54 ]. In a recent survey using a nasal epithelium (RPMI-2650) model, it was demonstrated that BPIFA1 expression was elevated after LPS-induced inflammation though the MEK/ERK pathway, and BPIFA1 expression was attenuated by IL-13 through the JNK and c-Jun signaling pathway [ 39 ] as shown in Figure 3 . Lactoferrin was shown to recover the suppressed BPIFA1 through downregulation of the MEK1/2-MAPK signaling pathway by preventing BPIFA1 degradation by LPS.…”

“…The surfactant function of BPIFA1 is demonstrated mainly in cystic fibrosis in the lower airway and is not widely reported in the mucosa of the upper airway. Furthermore, LPS-induced BPIFA1 expression in the upper airway is mainly involved in JNK/c-Jun [ 39 ] and MEK1/2-MARK pathway signaling [ 18 ], while the lower airway is mediated by MARK/AP-1 activation through the TLR2 pathway [ 54 ]. The lower airway attracted neutrophils and macrophages that could also secrete BPIFA1 and aid in innate immune protection of pulmonary tissue, a phenomenon that has not been reported in the upper airway.…”

Impact of Mycotoxins Secreted by Aspergillus Molds on the Inflammatory Response of Human Corneal Epithelial Cells

“…Contrary to this, the gene expression of CCL-2 was not induced by gliotoxin and was even decreased by AFB 1 ; as CCL-2 is a chemoattractant chemokine for monocytes [ 35 ], we can hypothesize monocytes to be less involved in the inflammation process following exposure to both mycotoxins. The gene expression of IL-13, a cytokine known to contribute to airway allergies [ 36 , 37 ], was not induced either. One would expect an induction of TLR-4 gene expression after direct exposure to fungi as the involvement of this receptor in the immune response to Aspergillus fumigatus was evidenced previously [ 38 , 39 ].…”