Tnfa and Il-10 Deficiencies Have Contrasting Effects on Lung Tumor Susceptibility: Gender-Dependent Modulation of IL-10 Haploinsufficiency

Heike Bernert, Kenji Sekikawa, Richard A. Radcliffe, Fuad Iraqi, Ming You, Alvin M. Malkinson

Research output: Contribution to journalArticlepeer-review

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 anti-inflammatory 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 II-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 II-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 II-10+/+ mice developed more tumors than did female mice (P<0.001), absence of one copy of II-10 raised tumor number in female mice to that observed in +/+ males, but no change in multiplicity occurred in II-70 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 II-10 haploinsufficiency is gender dependent. These studies support a role for inflammation in lung cancer susceptibility.

Original languageEnglish
Pages (from-to)117-123
Number of pages7
JournalMolecular Carcinogenesis
Volume38
Issue number3
DOIs
StatePublished - Nov 2003
Externally publishedYes

Keywords

  • Cytokines
  • Haploinsufficiency
  • Inflammation
  • Lung tumors
  • Quantitative trait loci

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