Tnfa and Il-10 deficiencies have contrasting effects on lung tumor susceptibility: gender-dependent modulation of IL-10 haploinsufficiency.
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.
Division of Human Cancer Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
Heike
H
Bernert
Kenji
K
Sekikawa
Richard A
RA
Radcliffe
Fuad
F
Iraqi
Ming
M
You
Alvin M
AM
Malkinson
D000483:Alleles; D000818:Animals; D001835:Body Weight; D004198:Disease Susceptibility; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017678:Sex Distribution; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics*; D014520:Urethane / Q000633:toxicity
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D014520:Urethane