Recruitment of Hepatic NK Cells by IL-12 Is Dependent on IFN-γ and VCAM-1 and Is Rapidly Down-Regulated by a Mechanism Involving T Cells and Expression of Fas

William E. Fogler, Kirk Volker, Morihiro Watanabe, Jon M. Wigginton, Philip Roessler, Michael J. Brunda, John R. Ortaldo and Robert H. Wiltrout
J Immunol December 1, 1998, 161 (11) 6014-6021;

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Alterations in the number and frequency of NK and T cells induced in the liver by administration of rmIL-12. C57BL/6 mice were injected i.p. daily with either 0.5 μg of rmIL-12 or 100,000 IU of human rIL-2 for 1–7 days. Leukocytes were isolated from the livers, and the numbers of NK1.1+, CD3− and NK1.1−, CD3+ cells were determined by FCA for IL-12 (A) or IL-2 (B). C depicts changes in the frequency of NK1.1+, CD3− cells on days 0, 1, and 4 in mice treated with IL-12. NK activity was determined as outlined in Materials and Methods.

  • FIGURE 2.
    FIGURE 2.

    Role of IFN-γ in IL-12-induced changes in hepatic NK cells. Wild-type C57BL/6 mice or C57BL/6 mice exhibiting targeted disruption of the IFN-γ gene (IFN-γ−/−) were injected i.p. with 0.5 μg of rmIL-12, 2.5 × 105 U of rmIFN-γ, or 100,000 IU of rhIL-2. Leukocytes were isolated 24 h later from the livers, and the number of NK1.1+, CD3− cells was determined.

  • FIGURE 3.
    FIGURE 3.

    Role of IFN-γ in IL-12-induced changes in hepatic T cells. Wild-type or IFN-γ−/−C57BL/6 mice were injected i.p. for 4 days with 0.5 μg of rmIL-12. Leukocytes were then isolated from the livers, and the number of NK1.1−, CD3+ cells was determined.

  • FIGURE 4.
    FIGURE 4.

    Role of VCAM-1 and ICAM-1 expression in IL-12-induced recruitment of NK and T cells to the liver. C57BL/6 mice were injected i.p. with 0.5 μg of rmIL-12 daily for 1 or 4 days. Some mice also received i.p. injections of 500 μg of α-VCAM-1, α-ICAM-1 mAb, or control rat IgG on days 1 or on days 1 and 3. Leukocytes were then isolated on day 1 for assessment of the effects on the number of NK1.1+, CD3− cells and on day 4 for assessment of the effects on the NK1.1−, CD3+ cell subset.

  • FIGURE 5.
    FIGURE 5.

    Kinetics of hepatic gene expression of ICAM-1 and VCAM-1 in mice treated with IL-12. C57BL/6 mice were injected i.p. daily for 1, 4, or 7 days with 0.5 μg of rmIL-12. Total liver RNA was extracted at various times, and ICAM-1 and VCAM-1 gene expression was detected by Northern blot analysis.

  • FIGURE 6.
    FIGURE 6.

    Relationship between IFN-γ induction and VCAM-1 and tVCAM-1 gene expression during rmIL-12 induction of hepatic cell infiltration. C57BL/6 wild-type and IFN-γ−/− mice were injected i.p. with 0.5 μg of rmIL-12. Twenty-four hours later the livers were harvested, total RNA was extracted, and Northern blot analysis of VCAM-1 gene expression was performed.

  • FIGURE 7.
    FIGURE 7.

    The disappearance of IL-12-induced hepatic NK cells is abrogated in SCID mice. C57BL/6 SCID mice were injected i.p. with 0.5 μg of rmIL-12 daily for 1 or 4 days, and the number of hepatic NK1.1+, CD3− cells was determined by FCA.

  • FIGURE 8.
    FIGURE 8.

    Persistence of IL-12-induced hepatic NK cells in B6.MRL-Faslpr (Fas−; A) and B6Smn.C3H-Faslgld (FasL−; B) mice. Mice were injected i.p. daily with 0.5 μg of rmIL-12 for 1 or 4 days. Leukocytes were isolated from the liver on days 1 and 4, and the number of NK1.1+, CD3− cells was determined by FCA.

  • FIGURE 9.
    FIGURE 9.

    Hepatic T cell infiltration in B6.MRL-Faslpr (Fas−; A) and B6Smn.C3H-Faslgld (FasL−; B) mice in response to IL-12. Mice were injected i.p. daily with 0.5 μg of rmIL-12 for 1 or 4 days. Leukocytes were isolated from the liver on days 1 and 4, and the number of NK1.1−, CD3+ cells was determined by FCA.

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The Journal of Immunology
Vol. 161, Issue 11
1 Dec 1998
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