Induction of long-lasting cytokine effect by injection of IL-12 encoding plasmid DNA.
We have recently demonstrated that DNA coding for both subunits of the murine IL-12 heterodimer exhibits a strong antimetastatic effect against B16-melanoma in C57BL/6 mice and after intratumoral injection tumor regression. Here we show that the antimetastatic effect can be detected when the DNA is injected intramuscularly 30 days before tumor cell challenge. A long-term IL-12 expression was measured for up to 50 days in the serum with a peak at day 20 amounting to about 10 ng/mL in C57BL/6 mice. CpG oligodeoxynucleotides also induce IL-12 expression, however, only for a few hours. IL-12 DNA administration induces long-lasting systemic IFN -gamma production, whereas IL-4 and TNF-alpha levels remained undetectable. NK cell-depleted mice showed a strong but reduced expression of murine IL-12. Expression of DNA encoding human instead of murine IL-12 resulted in a significantly lower and transient expression, indicating that not plasmid-derived IL-12 production alone but the immune system of the host contributes to the long- lasting antimetastatic effect. It may be attributable to an autocrine feedback mechanism maintaining murine IL- 12 expression, whereby several cell populations including NK cells are involved.
Institute of Medical Virology, University of Zurich, Switzerland.
J
J
Schultz
L
L
Heinzerling
J
J
Pavlovic
K
K
Moelling
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018899:CpG Islands / Q000235:genetics; D004247:DNA / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000628:therapy*; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019444:Vaccines, DNA / Q000627:therapeutic use*
D017931:DNA Primers; D019444:Vaccines, DNA; D018664:Interleukin-12; D007371:Interferon-gamma; D004247:DNA