Exposure to Cigarette Smoke Disrupts CCL20-Mediated Antimicrobial Activity in Respiratory Epithelial Cells

Abstract

Cigarette smoke (CS) exposure is known to increase infection rates, but the mechanisms are not well understood. These studies tested the hypothesis that CS exposure would impair antimicrobial activity of apical conditioned media from human airway (BEAS-2B) cultures by reducing induction and release of the antimicrobial peptide CCL20. BEAS-2B cultures were exposed to CS extract and assayed for temporal and physical characteristics of release as well as for antimicrobial activity. E. coli were exposed to Beas-2B-conditioned media (BCM) and subsequent bacterial colonies were enumerated. In time course studies TLR-agonist-induced CCL20 transcription and release were rapid, of short duration and release was consistently targeted to the apical/luminal compartment. Cells treated with CS extract had diminished release of CCL20 under both constitutive and toll-like receptor (TLR) agonist stimulating conditions. Exposure of the cells to CS significantly reduced the antimicrobial activity in BCM and neutralizing antibodies to CCL20 brought antibacterial activity back to baseline levels demonstrating that antimicrobial activity in this culture system was primarily attributable to CCL20. These studies add to the understanding of CCL20 as a mucosal antimicrobial and improve insight into a likely mechanism linking infection to CS exposure.

Developmental effects of tobacco smoke exposure during human embryonic stem cell differentiation are mediated through the transforming growth factor-β superfamily member, Nodal

“…We have shown that with gas chromatography, it is possible to deliver physiological concentrations of tobacco smoke components to hESCs. Our approach contrasts that of other groups who have exposed cell cultures to tobacco smoke without quantifying the concentration of nicotine or other components that were being delivered (Crane-Godreau et al, 2009; Nana-Sinkam et al, 2007). Although other studies have provided results indicating the potential effects of tobacco components on cells, it is quite possible that those studies introduced toxins at concentrations significantly above physiological levels.…”

SIRT1/FoxO3 axis alteration leads to aberrant immune responses in bronchial epithelial cells

“…In total lung homogenate and induced sputum of patients with COPD, CCL20 protein levels were significantly higher compared with never smokers and smokers without COPD . On the contrary, studies on CSE‐treated human bronchial epithelial cells and primary human nasal epithelial cells showed reduced CCL20 expression and impaired antimicrobial activity in response to CSE. CCL20 shares its antimicrobial activity with the human β‐defensin (HBD)‐2 which interact with the same membrane receptor, CCR6 .…”

Cigarette Smoke Exposure-Associated Alterations to Non-Coding RNA

“…Research in both model systems and human cohorts has suggested that a variety of environmental exposures have consequences for gene expression through epigenetic modes of gene regulation. Particular focus has been placed on four modes of epigenetic regulation, namely DNA methylation, imprinting, histone modifications, and ncRNA-mediated gene regulation (Crane-Godreau et al, 2009). While the study of DNA methylation remains the most widely studied mode of epigenetic regulation, the study of ncRNA-mediated gene regulation has gained significant attention over the past two decades.…”

“…Since partial or imperfect complementarity of a miRNA to a target mRNA can lead to translational repression which can effectively silence a gene, a single miRNA has the capability of regulating a large number of genes (Du and Zamore, 2007). By their mechanisms of negative regulation, miRNA have been shown to exhibit tissue-specific expression and function and play a role in regulating a wide range of biological processes, including differentiation, proliferation, apoptosis, and stress responses (Crane-Godreau et al, 2009). …”

“…During fetal development, the placenta is of utmost importance to ensuring the proper growth and development of the fetus; it provides the fetus with nutrients, aids in the elimination of waste products, and protects the fetus from a variety of environmental toxicants (Crane-Godreau et al, 2009; Maccani et al, 2010). Recently, Maccani et al (2010) used a candidate miRNA approach to investigate how maternal cigarette smoking during pregnancy might be associated with differential expression of miRNA in the placenta.…”