Natural killer cell is a major producer of interferon gamma that is critical for the IL-12-induced anti-tumor effect in mice.
Although the anti-tumor effect of IL-12 is mediated mostly by IFNgamma, which cell types most efficiently produce IFNgamma and therefore initiate or promote the anti-tumor effect of IL-12 has not been clearly determined. In the present study, we demonstrated hydrodynamic injection of the IL-12 gene led to prolonged IFNgamma production, NK-cell activation and complete inhibition of liver metastasis of CT-26 colon cancer cells in wild-type mice, but not in IFNgamma knockout mice. NK cells expressed higher levels of STAT4 and upon IL-12 administration displayed stronger STAT4 phosphorylation and IFNgamma production than non-NK cells. Adoptive transfer of wild-type NK cells into IFNgamma knockout mice restored IL-12-induced IFNgamma production, NK-cell activation and anti-tumor effect, whereas transfer of the same number of wild-type non-NK cells did not. In conclusion, NK cells are predominant producers of IFNgamma that is critical for IL-12 anti-tumor therapy.
Uemura
Akio
A
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Yamada-oka, Suita, Japan. akioue@gh.med.osaka-u.ac.jp
Takehara
Tetsuo
T
Miyagi
Takuya
T
Suzuki
Takahiro
T
Tatsumi
Tomohide
T
Ohkawa
Kazuyoshi
K
Kanto
Tatsuya
T
Hiramatsu
Naoki
N
Hayashi
Norio
N
D019264:Adoptive Transfer; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology* / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007371:Interferon-gamma; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D050797:STAT4 Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma