Tnfa and Il‐10 deficiencies have contrasting effects on lung tumor susceptibility: Gender‐dependent modulation of IL‐10 haploinsufficiency
- 23 October 2003
- journal article
- research article
- Published by Wiley in Molecular Carcinogenesis
- Vol. 38 (3), 117-123
- https://doi.org/10.1002/mc.10151
Abstract
Epidemiologic evidence suggests that pulmonary diseases with a prominent chronic inflammatory component elevate lung cancer risk. Genetic manipulations of mouse models of lung inflammation and tumorigenesis can be used to investigate this association. The genes encoding pro‐inflammatory tumor necrosis factor‐α (TNFα) and antiinflammatory IL‐10 cytokines map within quantitative trait loci that regulate susceptibility to lung tumor development in mice; sensitive A/J and resistant C57BL/6J (B6) mice have different Tnfa and Il‐10 alleles. Genetic ablation studies were performed to examine whether these genes would qualify as candidate tumor modifiers. Tnfa null (−/−) mice on a B6 background and B6.129 Il‐10−/− mice were intercrossed with A/J mice and subjected to urethane carcinogenesis; lung tumor multiplicity was determined 20 weeks later. In the absence of one copy of Tnfa, tumor number. Male Il‐10+/+ mice developed more tumors than did female mice (P < 0.001), absence of one copy of Il‐10 raised tumor number in female mice to that observed in +/+ males, but no change in multiplicity occurred in Il‐10 hemizygous males. Thus, a deficit of pro‐inflammatory TNFα decreased the number of tumors, whereas diminished gene copy number of anti‐inflammatory IL‐10 increased tumorigenesis; manifestation of an effect of Il‐10 haploinsufficiency is gender dependent. These studies support a role for inflammation in lung cancer susceptibility.Keywords
This publication has 56 references indexed in Scilit:
- Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumorsNature Genetics, 2003
- Mouse Strain Modulates the Role of the Ciliated Cell in Acute Tracheobronchial Airway Injury-Distal AirwaysThe American Journal of Pathology, 2002
- Cancer as a Complex Genetic Trait: Tumor Susceptibility in Humans and Mouse ModelsCell, 2002
- Women and lung cancer: does oestrogen play a role?The Lancet Oncology, 2001
- The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64Oncogene, 2000
- Ki-ras and p53 mutations are early and late events, respectively, in urethane-induced pulmonary carcinogenesis in A/J miceMolecular Carcinogenesis, 1996
- Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses.JCI Insight, 1996
- The intronic structure of cancer-related genes regulates susceptibility to cancerMolecular Carcinogenesis, 1994
- A major susceptibility locus to murine lung carcinogenesis maps on chromosome 6Nature Genetics, 1993
- The genetic basis of susceptibility to lung tumors in miceToxicology, 1989