title: Aryl hydrocarbon receptor (AhR) regulates silica-induced inflammation but not fibrosis.
abstract: The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is responsible for mediating a variety of pharmacological and toxicological effects caused by halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, recent evidence has revealed that the AhR also has numerous physiological roles aside from xenobiotic metabolism, including regulation of immune and inflammatory signaling as well as normal development and homeostasis of several organs. To investigate the role of the AhR in crystalline silica (SiO(2))-induced inflammation and fibrosis, C57Bl/6 and AhR(-/)(-) mice were exposed to SiO(2) or vehicle. Similarly, C57Bl/6 mice were exposed to SiO(2) and TCDD either simultaneously or sequentially to assess whether AhR activation alters inflammation and fibrosis. SiO(2)-induced acute lung inflammation was more severe in AhR(-)(/-) mice; however, the fibrotic response of AhR(-)(/-) mice was attenuated compared with C57Bl/6 mice. In a model of chronic SiO(2) exposure, AhR activation by TCDD in C57Bl/6 mice resulted in reduced inflammation; however, the fibrotic response was not affected. Bone marrow-derived macrophages (BMM) from AhR(-)(/-) mice also produced higher levels of cytokines and chemokines in response to SiO(2). Analysis of gene expression revealed that BMM derived from AhR(-)(/-) mice exhibit increased levels of pro-interleukin (IL)-1β, IL-6, and Bcl-2, yet decreased levels of signal transducers and activators of transcription (STAT)2, STAT5a, and serpin B2 (Pai-2) in response to SiO(2).
authors.affiliation: Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, Montana 59812, USA. celine.beamer@umontana.edu
authors.forename: Celine A
authors.initials: CA
authors.lastname: Beamer
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Seaver
authors.forename: David M
authors.initials: DM
authors.lastname: Shepherd
mesh_terms: D000818:Animals; D005434:Flow Cytometry; D007249:Inflammation / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011658:Pulmonary Fibrosis / Q000139:chemically induced*; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D012822:Silicon Dioxide / Q000633:toxicity*
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D012822:Silicon Dioxide