ABSTRACT: We previously reported that administration into mice of mouse lymphoid leukemia L1210 cells engineered to secrete macrophage
colony-stimulating factor (M-CSF) could lead to tumor rejection. Here, we demonstrate that inoculation with irradiated M-CSF-producing
cells protects mice against a subsequent challenge with unmodified parental tumor cells. We used 2 experimental protocols:
the inoculation with irradiated M-CSF-producing L1210 cells (EM5) before the challenge with parental cells and after the challenge
with parental cells. Both protocols effectively improved the survival rate of mice compared with protocols in which irradiated
non-M-CSF-producing L1210 cells (EM-mock) were inoculated. Inoculation with 1 X 102 irradiated EM5 cells was sufficient to prolong the survival time of mice subsequently challenged with 1 X 104 parental cells. In vivo depletion experiments with administration of antibodies suggested the involvement of CD4+ T cells, CD8+ T cells, and natural killer (NK) cells in the antitumor effect. Consistent with these findings, the cytotoxic T lymphocyte
activity of splenocytes from EM5-inoculated mice was higher than that from EM-mock-inoculated mice, and L1210 tumors were
heavily infiltrated by CD4+ T cells and NK cells as well as macrophages in EM5-inoculated mice.
International Journal of Hematology 04/2012; 73(3):378-382. · 1.27 Impact Factor
ABSTRACT: The purpose of this study was to evaluate the effect of coadministration of macrophage colony-stimulating factor (M-CSF) and interferon-alpha (IFN-alpha) on NK1.1(+) cells in mice. Administration of M-CSF, but not IFN-alpha, increased the number of NK1.1(+) cells and CD11b(+) cells in spleen and blood. Coadministration of the two agents induced a greater increase in NK1.1(+) cells than did administration of M-CSF alone. Administration of M-CSF or IFN-alpha augmented the clearance activity of Yac-1 cells in lung, and coadministration of these agents further augmented this effect. The combination of M-CSF and IFN-alpha effectively reduced the formation of tumor nodules in lung and liver in an experimental metastasis model using B16 melanoma. The combination of M-CSF and IFN-alpha induced the increase and activation of NK1.1(+) cells more than either agent alone. These effects may contribute to the antimetastatic reaction by NK1.1(+) cells in vivo.
Journal of Interferon & Cytokine Research 07/2002; 22(6):701-8. · 3.06 Impact Factor
ABSTRACT: p56dok-2 acts as a multiple docking protein downstream of receptor or non-receptor tyrosine kinases. However, the role of p56dok-2 in biological functions of cells is not clear. We found that transcription of the p56dok-2 gene in macrophages was increased markedly in response to cytokines such as macrophage colony-stimulating factor (M-CSF), granulocyte/macrophage-CSF and interleukin-3 (IL-3). Forced expression of p56dok–2 inhibited M-CSF-, granulocyte-CSF-, IL-3- and stem cell factor-induced proliferation of myeloid leukemia cells, M-NFS-60. The p56dok-2-overexpressing cells showed an impaired induction of c-myc but not of c-jun, junB or c-fos when stimulated with M-CSF. Consistent with these results, the peritoneal cavity of the hairless (hr/hr) strain of mutant mice, whose cells expressed less p56dok-2 than wild-type mice, contained more macrophages than that of +/hr mice. Moreover, the inhibition of endogenous p56dok-2 expression in macrophage-like tumor cells, J774A.1, by stable expression of antisense p56dok-2 mRNA accelerated cell proliferation. The study identifies a novel role for p56dok-2 as a molecule that negatively regulates signal transduction and cell proliferation mediated by cytokines in a feedback loop.
The EMBO Journal 10/2000; 19(19):5114-5122. · 9.20 Impact Factor