title: Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis.
abstract: Because chronic pulmonary diseases predispose to lung neoplasia, the identification of the molecular mechanisms involved could provide novel preventive, diagnostic, and therapeutic strategies. Toll-like receptors (TLRs) transduce exogenous and endogenous signals into the production of inflammatory cytokines to coordinate adaptive immune responses. To determine the role of Tlr4 in chronic lung inflammation, we compared lung permeability, leukocyte infiltration, and nuclear factor kappa B (NFkappaB) and activator protein 1 (AP-1) DNA binding in butylated hydroxytoluene (BHT)-treated (four weekly injections of 125-200 mg/kg each) inbred mouse strains with functional Tlr4 (OuJ and BALB) and mutated Tlr4 (HeJ and BALB(Lps-d)). We also measured primary tumor formation in these mice after single-carcinogen injection (3-methylcholanthrene; 10 microg/kg), followed by BHT treatment (six weekly injections of 125-200 mg/kg each). Mice with functional Tlr4 had reduced lung permeability, leukocyte inflammation, and primary tumor formation (BALB(Lps-d), mean = 22.3 tumors/mouse, versus BALB, mean = 13.9 tumors/mouse, difference = 8.4 tumors/mouse, 95% confidence interval = 4.6 to 12.1 tumors/mouse; P = .025) compared with mice with mutated Tlr4. NFkappaB DNA binding activity was higher in OuJ than in HeJ mice; however, AP-1 activity was elevated in HeJ mice. To our knowledge, this is the first model to demonstrate a modulatory role for Tlr4 in chronic lung inflammation and tumorigenesis.
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. bauer1@niehs.nih.gov
authors.forename: Alison K
authors.initials: AK
authors.lastname: Bauer
authors.forename: Darlene
authors.initials: D
authors.lastname: Dixon
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.forename: Hye-Youn
authors.initials: HY
authors.lastname: Cho
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Walker
authors.forename: Alvin M
authors.initials: AM
authors.lastname: Malkinson
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
mesh_terms: D000818:Animals; D002084:Butylated Hydroxytoluene; D004195:Disease Models, Animal; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D002084:Butylated Hydroxytoluene