Interleukin-18 in combination with IL-2 enhances natural killer cell activity without inducing large amounts of IFN-gamma in vivo.
Interleukin-18 (IL-18) is known to synergistically enhance murine natural killer (NK) cell activity in vitro when combined with either IL-12 or IL-2. However, it has also been demonstrated that simultaneous administration of IL-18 and IL-12 to mice induces extraordinarily large amounts of interferon-gamma (IFN-gamma) in the serum. In this study, we examined the effects of a combination of IL-18 and IL-2 on in vivo NK cell activation in parallel with the induction of toxicity. In contrast to the IL-18 and IL-12 combination, the combined administration of IL-18 and IL-2 to BALB/c mice for 3 days induced neither high levels of IFN-gamma production nor other visible side effects. When compared with treatment with IL-18 or IL-2 alone, the combined treatment resulted in a significant increase in the number of DX-5 (pan-NK cells marker)-positive cells in spleens and a marked enhancement of splenic NK activity, as determined by standard cytotoxicity assays. Enhanced splenic cytotoxicity generated in the mice treated with both IL-18 and IL-2 was also observed against syngeneic Colon 26 adenocarcinoma cells. Consistent with this in vitro observation, combined treatment produced a significantly stronger inhibitory effect on the pulmonary metastases following i.v. injection of Colon 26 tumor cells than treatment with either cytokine alone. These results suggest that IL-18 combined with IL-2 potentiates in vivo NK cell activity and contributes to inhibition of tumor metastasis without inducing significant toxicity.
Arai
N
N
Fujisaki Institute, Hayashibara Biochemical Laboratories Inc., Okayama, Japan.
Akamatsu
S
S
Arai
S
S
Toshimori
Y
Y
Hanaya
T
T
Tanimoto
T
T
Ikeda
M
M
Tomura
M
M
Fujiwara
H
H
Kurimoto
M
M
D000818:Animals; D004357:Drug Synergism; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000008:administration & dosage; D020382:Interleukin-18 / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000008:administration & dosage; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured
D020382:Interleukin-18; D007376:Interleukin-2; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma