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Mol Carcinog. 2003 Nov;38(3):117-23.

Tnfa and Il-10 deficiencies have contrasting effects on lung tumor susceptibility: gender-dependent modulation of IL-10 haploinsufficiency.

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  • 1Division of Human Cancer Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.

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-alpha (TNFalpha) 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 TNFalpha 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.

PMID:
14587096
DOI:
10.1002/mc.10151
[PubMed - indexed for MEDLINE]
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