A dual role for the immune response in a mouse model of inflammation-associated lung cancer
Michael Dougan, … , Kwok-Kin Wong, Glenn Dranoff
Michael Dougan, … , Kwok-Kin Wong, Glenn Dranoff
Published May 2, 2011
Citation Information: J Clin Invest. 2011;121(6):2436-2446. https://doi.org/10.1172/JCI44796.
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Research Article Oncology

A dual role for the immune response in a mouse model of inflammation-associated lung cancer

Abstract

Lung cancer is the leading cause of cancer death worldwide. Both principal factors known to cause lung cancer, cigarette smoke and asbestos, induce pulmonary inflammation, and pulmonary inflammation has recently been implicated in several murine models of lung cancer. To further investigate the role of inflammation in the development of lung cancer, we generated mice with combined loss of IFN-γ and the β-common cytokines GM-CSF and IL-3. These immunodeficient mice develop chronic pulmonary inflammation and lung tumors at a high frequency. Examination of the relationship between these tumors and their inflammatory microenvironment revealed a dual role for the immune system in tumor development. The inflammatory cytokine IL-6 promoted optimal tumor growth, yet wild-type mice rejected transplanted tumors through the induction of adaptive immunity. These findings suggest a model whereby cytokine deficiency leads to oncogenic inflammation that combines with defective antitumor immunity to promote lung tumor formation, representing a unique system for studying the role of the immune system in lung tumor development.

Authors

Michael Dougan, Danan Li, Donna Neuberg, Martin Mihm, Paul Googe, Kwok-Kin Wong, Glenn Dranoff

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Figure 6

Inhibition of NF-κB signaling in a BALB/c TKO lung tumor cell line leads to rapid loss of viability.

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Inhibition of NF-κB signaling in a BALB/c TKO lung tumor cell line leads...
(A) Western blot of nuclear lysates from MDAC8 cells cultured for 1 hour with an IKK2 inhibitor (IKK2i), a combined IKK1-IKK2 inhibitor (IKK1/2i), or vehicle (DMSO); Data in A and B represent samples analyzed from 2 independent cultures. (B) 3 × 105 MDAC8 cells were cultured for 72 hours with IKK inhibitors, vehicle (DMSO), or media (No Tx); IKK2 inhibitor I is identical to IKK2i in A, and IKK1/2 inhibitor II is identical to IKK1/2i in A; relative cell numbers were determined using CTG, with the average reading for the untreated group defined as 1. (C) Time course of cell loss following IKK inhibitor treatment; cells were treated as in B and analyzed using CTG; the average reading for the untreated group at time 0 was defined as 1. (D) Dose response to IKK1/2 inhibitor II after 72 hours; cells were treated and analyzed as in B. (E) IL-6 production from MDAC8 cells treated with IKK inhibitors as in B; IL-6 was measured by ELISA. (B–E) Results are representative of 2–3 independent experiments, with 6 replicates per group. Error bars represent SEM. All IKK inhibitors were from EMD Biosciences and were used at the following concentrations unless otherwise indicated: IKK2 inhibitor I (EMD IKK-2 Inhibitor IV), 10 μM; IKK2 inhibitor II (EMD IKK-2 Inhibitor VI), 5 μM; IKK1/2 inhibitor I (BMS-345541), 40 μM; IKK1/2 inhibitor II (EMD IKK Inhibitor VII), 20 μM.