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

Mol Carcinog. 2003 Nov;38(3):117-23. doi: 10.1002/mc.10151.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Body Weight
  • Disease Susceptibility
  • Female
  • Gene Deletion*
  • Heterozygote
  • Homozygote
  • Interleukin-10 / deficiency
  • Interleukin-10 / genetics*
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Sex Distribution
  • Tumor Necrosis Factor-alpha / deficiency
  • Tumor Necrosis Factor-alpha / genetics*
  • Urethane / toxicity


  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Urethane