Arylhydrocarbon receptor activation in NCI-H441 cells and C57BL/6 mice: possible mechanisms for lung dysfunction.
The arylhydrocarbon receptor (AhR) is known for its ability to bind aromatic-containing compounds, which starts a molecular cascade involving the induction of cytochrome P450s and inflammatory cytokines. Our hypothesis is that many inhaled environmental toxicant components activate these inflammatory pathways via an initial binding to the AhR. To test this possibility, we treated Clara cell-derived NCI-H441 cells with the AhR agonist, 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD), and demonstrated that AhR activation increased the expression of both cytochrome P450 s and inflammatory markers. We also found increased mucin 5AC production with TCDD treatment. Similar results were observed in NCI-H441 cells treated with urban dust particles. Mucin 5AC expression was highly correlated with increased-expression cyclooxygenase-2 and IL-1beta, thus implicating these two inflammatory markers as possible conduits for AhR-mediated mucin production. We hypothesize that this increase in mucin 5AC production is a result of inflammation-induced differentiation of our epithelial cell to a mucin-producing cell. This theory is supported by morphological changes observed in the cells, as well as decreased expression of Clara cell secretory protein (CC10). In an in vivo C57BL/6 mouse model, TCDD increased expression of inflammatory cytokines, mucin 5AC, and a number of matrix metalloproteases in whole-lung samples. These changes were not seen in mice in which AhR signaling was repressed. These markers from the whole-lung samples have been correlated to onset of bronchitis, asthma, small airways disease, and fibrosis, and their increased expression further implicates AhR activation in producing the molecular environment for the development of lung injury to occur.
Wong
Patrick S
PS
Center for Health and the Environment, University of California at Davis, 1 Shields Avenue, Davis, CA 95616, USA. patwong@ucdavis.edu
Vogel
Chris F
CF
Kokosinski
Katherine
K
Matsumura
Fumio
F
D000393:Air Pollutants / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D055271:Mucin 5AC / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics; D014598:Uteroglobin / Q000235:genetics
D000393:Air Pollutants; D053583:Interleukin-1beta; D055271:Mucin 5AC; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; D014598:Uteroglobin; D019363:Cytochrome P-450 CYP1A1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2