Journal Article

Toll-Like Receptor 4 in Butylated Hydroxytoluene–Induced Mouse Pulmonary Inflammation and Tumorigenesis

Alison K. Bauer, Darlene Dixon, Laura M. DeGraff, Hye-Youn Cho, Christopher R. Walker, Alvin M. Malkinson and Steven R. Kleeberger

in JNCI: Journal of the National Cancer Institute

Volume 97, issue 23, pages 1778-1781
Published in print December 2005 | ISSN: 0027-8874
Published online December 2005 | e-ISSN: 1460-2105 | DOI: http://dx.doi.org/10.1093/jnci/dji403
Toll-Like Receptor 4 in Butylated Hydroxytoluene–Induced Mouse Pulmonary Inflammation and Tumorigenesis

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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 (NFκB) 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 BALBLps–d). We also measured primary tumor formation in these mice after single-carcinogen injection (3-methylcholanthrene; 10 μg/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 (BALBLps–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. NFκB 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.

Journal Article.  2494 words.  Illustrated.

Subjects: Medical Oncology

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