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Departments of
*
Surgery and
Molecular Genetics and Biochemistry, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
Division of Host Defense, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Hyogo, Japan;
§
Fujisaki Institute, Hayashibara Biochemical Laboratories, Okayama, Japan; and
¶
Department of Genetics, Osaka University Medical School, Osaka, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, a
cytokine that is induced by IL-18 in vitro and in vivo. We conclude
that the antitumor effect of IL-18 is exerted predominantly through a
Fas-dependent pathway. The perforin pathway, however, appears to be the
predominant cytolytic pathway mediating IL-12 antitumor
effects. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducing factor (IGIF) based on its ability to induce high
level IFN- secretion by both NK and T cells (1, 2).
IL-18 mediates other important functions, including enhancement of NK
cell activity and stimulation of proliferation of activated T cells
(1, 2, 3, 4, 5). Recent reports have suggested that IL-18 affects
the development of cellular immunity (Th1 response) following Ag
presentation (6). It also potentiates IL-12-driven Th1
development in BALB/c mice and, with IL-12, promotes IFN- production
from Th1 cells in a synergistic fashion. Unlike IL-12, IL-18 alone does
not drive Th1 development in BALB/c or C57BL/6 mice. Studies of
IL-18-deficient mice support the notion that IL-18 does play an
important supportive role in Th1 development (7).
IL-18-deficient mice have normal IL-12 induction but markedly reduced
IFN- production following LPS stimulation subsequent to
Propionibacterium acnes priming. Significantly impaired NK
cell activity and reduced Th1 cell response after injection of P.
acnes or Mycobacterium bovis are also noted in these
mice. In mice lacking both IL-18 and IL-12 production, markedly
impaired NK activity and Th1 responses are noted. Th1 response could be
reconstituted by IL-12 administration but not in IL-18-treated animals.
In addition to these functions, IL-18 also enhances expression of Fas
ligand (FasL)4 on NK
(8) and Th1 clones (9) in mice and on
myelomonocytic cells in humans (10).
We and others have shown that rIL-18 has significant antitumor effects
in multiple murine tumor models (11, 12). In addition, we
have also shown that IL-18 could be utilized as a cancer gene therapy,
especially when combined with systemic administration of IL-12
(13). Interestingly, the antitumor effects of systemic
rIL-18 administration were retained, although diminished, in IFN- or
IL-12 gene-disrupted animals and were completely abrogated by
administration of anti-asialo GM1 Abs (12). These
results suggested that rIL-18 antitumor effects were mediated primarily
by asialo GM1+ cells in an IFN--independent
fashion.
Cytotoxicity of NK cells against tumor appears to be mediated by apoptosis induced by delivery of perforin/granzyme or Fas cross-inking by FasL (14). IL-12 enhances the cytolytic activity of NK-like cells primarily by inducing expression of perforin (15, 16). Thus, it was of interest to determine how NK cells mediate IL-18-induced antitumor effects. We hypothesized that IL-18 antitumor effects were mediated by Fas-FasL-induced apoptosis of tumor cells since IL-18 has been reported to enhance FasL expression on NK cell lines (8). We examined the IL-18-mediated antitumor effects on growth of subcutaneous tumor in generalized lymphoproliferative disease gene (gld) (FasL-deficient), lymphoproliferation gene (lpr) (Fas-deficient), and perforin gene-disrupted animals in vivo and in vitro. We demonstrate here that the antitumor effects of rIL-18 are completely absent in gld mice whereas IL-12 antitumor activity is retained in both gld and lpr mice. In addition, rIL-18 stimulates the cytolytic activity of lymphocytes from wt mice, but not gld mice. These results demonstrate that Fas-mediated tumor apoptosis plays a critical role in the antitumor effects mediated by rIL-18 but not that of rIL-12. Thus, the major role of IL-18 is to modulate innate effector immune mechanisms that subsequently enhance the induction of the specific adaptive antitumor immune response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Murine rIL-18 was kindly supplied by Hayashibara Biochemical
Laboratories (Okayama, Japan). Murine rIL-12 was a gift from Genetics
Institute (Cambridge, MA). Murine rIFN- was purchased from
PharMingen (San Diego, CA).
Tumor cell lines and animals
CL8-1 is a murine melanoma cell line derived from C57BL/6 mice and was generously provided by Dr. Gorelik (University of Pittsburgh, Pittsburgh, PA). This cell line was maintained as described previously (17) and was demonstrated to be free of mycoplasma contamination periodically. Wild type (wt) C57BL/6 mice were purchased from Taconic Farms (Germantown, NY). The gld (FasL-deficient), lpr (Fas-deficient), perforin -/-, and scid/scid C57BL/6 mouse strains were purchased from The Jackson Laboratory (Bar Harbor, ME). These animals were maintained in the animal facility at the Center for Biotechnology and Bioengineering, University of Pittsburgh, and were used for experiments when they were 7 to 10 wk old.
Animal experiments
All the animals were randomized and ear tagged before the experiments. Experiments were performed in a blinded fashion. CL8-1 cells (1 x 106) were inoculated intradermally (i.d.) in the flank of mice on day 0 in groups of five animals. Mice received once daily i.p. injections of rIL-18, rIL-12, or HBSS (Life Technologies, Grand Island, NY) on days 0 to 7. Tumor size was measured every 2 to 4 days, and the tumor volume was calculated using the formula 0.5 x A x B2 (A=largest diameter; B=smallest diameter). Each experiment was confirmed in at least one other experiment, and the results of a representative experiment are shown.
Preparation of mononuclear cells
Under deep ether anesthesia, mice were euthanized by exsanguination through the subclavian artery and vein. In addition to blood, the liver and spleen were harvested. The spleen was pressed through sterile gauze and washed, and the cell pellet was treated with RBC lysis solution (0.83% NH4Cl) and rinsed twice. Hepatic mononuclear cells (MNCs) were prepared essentially as described by Goossens et al. (18). In brief, the liver was passed through stainless steel mesh, and MNCs were rinsed twice and were resuspended in 32% Percoll containing 100 U/ml heparin. Following centrifugation at 2000 rpm for 10 min at room temperature, the pellet was resuspended in RBC lysis solution and then rinsed twice in 5% FCS-HBSS.
Cytotoxicity assay
YAC-1 (lymphoma cells of A/S [H-2a] origin), CL8-1, and L5178Y (T cell lymphoma derived from DBA/2 mice [H-2d]) were used as target cells. Target cells were propagated in culture, labeled with 100 µCi Na2(51Cr)O4 for 60 min at 37°C in RPMI 1640 medium containing 10% FCS, washed three times with medium, and placed in cytotoxicity assays. Labeled targets (103/well) were incubated in a total volume of 200 µl with effector cells in 10% FCS RPMI 1640 in 96-well round bottom microtiter plates. The plates were centrifuged before incubation, and, after 4h of incubation, the supernatant was harvested and measured in a gamma counter. The cytotoxicity was calculated as the percentage of releasable counts after subtraction of spontaneous. The spontaneous release was less than 15% of the maximum release.
Murine FasL expression in splenocytes by RT-PCR
Mice were treated with 1 µg of IL-18 for 2 days; after being sacrificed, the splenocytes were harvested. Total cellular RNA was extracted from whole MNCs using RNAzolB (Tel-Test, Friendswood, TX). Four micrograms of total RNA was reverse transcribed using an RNase H-reverse transcriptase (Superscript; Life Technologies). Two hundred nanograms of RNA-equivalent cDNA was used as a template for PCR. Amplification for FasL and ß-actin was performed 22 cycles consisting of 94°C for 1 min for denaturing, 57°C for 1 min for annealing, and 74°C for 1 min for extension. The sequences of primers for FasL (19) and ß-actin are as follows: FasL, 5'-CTA CCA CCG CCA TCA CAA C-3' and 5'-CCT CTT CTC CTC CAT TAG CAC-3'; ß-actin, 5'-TTCTACAATGAGCTGCGTGTG-3' and 5'-CACTGTGTTGGCATAGAGGTC-3'. Amplified products were electrophoresed on a 1.8% agarose gel and visualized with ethidium bromide staining.
Effects of an anti-Fas agonistic Ab on CL8-1 cell death
To determine whether the Fas Ag expressed on CL8-1 cells is
functional, 1 x 106 CL8-1 cells were seeded
in 12-well plates and incubated for 30 h at 37°C with an
agonistic Ab (Jo2; PharMingen; 1 µg/ml) against the Fas Ag with or
without IFN- (50 ng/ml). The percentage of dead cells was determined
by flow cytometer after propidium iodide (PI) staining.
Statistical evaluation
Nonparametric Wilcoxon test was used in the statistical analysis of the size of tumor. Student’s t test accompanied with F test was used in the statistical analysis of the in vitro cytotoxicity assay. The difference was considered statistically significant when the p value was less than 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously reported that administration of rIL-18
significantly suppresses the growth of CL8-1 murine melanoma cells.
Recently, IL-18 has been shown to enhance FasL expression on NK cells
(8). To examine the role of Fas-FasL-mediated apoptosis in
this model, 1 x 106 CL8-1 cells were inoculated i.d.
on day 0 in C57BL/6 wt, lpr, or gld mice,
and 1 µg of rIL-18 was injected i.p. daily for 7 days from day 0.
Although rIL-18 administration significantly suppressed the growth of
CL8-1 cells in C57BL/6 wt and lpr mice (wt/HBSS vs
wt/IL-18, on day 15 through day 30, p < 0.05;
lpr/HBSS vs lpr/IL-18, on day 6 through
day 21, p < 0.05), antitumor effects of rIL-18
were absent in gld mice (gld/HBSS vs
gld/IL-18, on day 21, p = 0.36;
wt/IL-18 vs gld/IL-18, on day 9 through day 30,
p < 0.05) (Fig. 1
A). In contrast, IL-12
administration greatly suppressed the growth of CL8-1 cells even in
gld mice (gld/HBSS vs
gld/IL-12, on day 9 through day 30,
p < 0.05; wt/IL-12 vs gld/IL-12, on
day 30, p = 0.77) (Fig. 1B). These
results strongly suggest that the antitumor effects of rIL-18, but not
rIL-12, administration are primarily mediated by the Fas-FasL
pathway.
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To examine whether the Fas-FasL pathway is responsible for the in
vitro cytotoxic activity induced by in vivo administration of rIL-18,
we examined the cytotoxicity of splenic and hepatic MNCs harvested from
C57BL/6 wt and gld mice after rIL-18 administration
against YAC-1 (NK-sensitive) and CL8-1 target cells. The rIL-18
administration greatly augmented the in vitro cytotoxic activities of
splenic (wt/HBSS vs wt/IL-18, p < 0.05 (all
points)) and hepatic (wt/HBSS vs wt/IL-18, p <
0.01 (all points)) MNCs against YAC-1 cells in wt, but the augmentation
was significantly reduced in gld mice (wt/IL-18 vs
gld/IL-18, p < 0.05 (all points) in
both splenic and hepatic MNCs) (Fig. 2A). Similar results were
identified when CL8-1 cells were used as target cells (Fig. 2B). On the other hand, rIL-12 administration augments
the in vitro cytotoxicity of splenic and hepatic MNCs against YAC-1 and
CL8-1 cells in both wt (wt/HBSS vs wt/IL-12, p <
0.05 (all points) in both splenic and hepatic MNCs) and
gld mice (gld//HBSS vs
gld/IL-12, p < 0.01 (all points) in
splenic MNCs and p < 0.05 (all points) in hepatic
MNCs) (Fig. 3 A and
B). Furthermore, rIL-12 administration augmented the
cytotoxic activity of hepatic MNCs against Fas-negative target cells
(L5178Y), whereas rIL-18 administration did not (data not shown).
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IL-12 enhances the cytotoxicity of NK cells (20),
NK1+ T cells (15, 16, 21, 22), and
CD8+ CTL (23). Recently, it has been reported
that the induction of perforin synthesis and subsequent release may be
responsible for the IL-12-induced cytotoxic activity of
NK1+ T cells (15, 16). To examine the role of
perforin-mediated cytotoxicity, we tested the in vitro cytotoxicity of
hepatic MNCs against YAC-1 target cells following rIL-12 or rIL-18
administration in C57BL/6 wt or perforin-deficient mice. Although the
enhancement of cytotoxic activity induced by rIL-12 administration to
wt mice (wt/HBSS vs wt/IL-12, p < 0.05 (all
points)) was completely absent in perforin-deficient mice (PKO/HBSS vs
PKO/IL-12, p > 0.05 (all points); wt/IL-12 vs
PKO/IL-12, p < 0.05 (all points)), that induced by
rIL-18 administration (wt/HBSS vs wt/IL-18, p <
0.01 (all points)) was still detectable but significantly reduced
(PKO/HBSS vs PKO/IL-18, p < 0.05 (all points);
wt/IL-18 vs PKO/IL-18, p < 0.05 (all points))
(Fig. 4). These results suggest that in
vitro cytotoxicity augmented by rIL-12, but not rIL-18, is mediated
almost totally by the perforin pathway.
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To determine whether IL-18 up-regulates FasL expression in
splenocytes, mRNA was analyzed by RT-PCR. Splenocytes were harvested
from C57BL/6 wt mice or SCID/SCID mice (SCID) following
administration of 1 µg of rIL-18 inoculation for two days without
further cell separation. FasL gene expression could not be detected in
splenocytes of wt mice following rIL-18 administration by RT-PCR
perhaps because of the limited sensitivity of our method. To examine
IL-18-induced up-regulation of FasL expression specifically in NK cells
avoiding the influence of B and T cells in bulk splenocyte preparation,
splenocytes were harvested from SCID mice who have a relatively higher
proportion of NK cells in the spleen (24). As shown in
Fig. 5, the expression of FasL mRNA in
SCID mouse splenocytes was augmented by rIL-18, suggesting that IL-18
induces up-regulation of FasL expression on NK cells.
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To determine whether the Fas Ag expressed on CL8-1 cells is
functional, the anti-Fas agonistic Ab (Jo2) was incubated with
CL8-1 cells in vitro, and the intensity of PI staining was measured to
examine the extent of Fas-induced cell death. Treatment with the
anti-Fas Ab indeed induced death of CL8-1 cells, confirming that
CL8-1 tumor cells are susceptible to Fas-mediated events (Fig. 6 A and B).
Interestingly, this Fas-mediated cytotoxicity of CL8-1 cells was
up-regulated by incubation with IFN- (Fig. 6, C and
D). This was also confirmed by staining with the
anti-Fas Ab, that IFN- stimulation could up-regulate Fas
expression on CL8-1 cells (Fig. 6E). These results
demonstrated that Fas-mediated cytotoxicity could be significantly
enhanced through up-regulation of Fas expression on target cells by
IFN-, which in turn is induced by IL-18 stimulation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). To
evaluate the role of perforin pathways in the IL-18-induced antitumor
effects, we evaluated the cytolytic activity in perforin gene-disrupted
mice. Although IL-12-induced cytotoxicity was completely abrogated in
this perforin-deficient system, IL-18- induced cytotoxicity
significantly remained (Fig. 4). Furthermore, RT-PCR analysis revealed
that rIL-18 administration up-regulated FasL expression on splenic NK
cells (Fig. 5). We also demonstrated that Fas-mediated killing of
target cells could be augmented by incubation with IFN-, which can
be induced by IL-18 (Fig. 6).
Since IL-18 is known to share several biological functions with IL-12,
including the induction of IFN- production and enhancement of
NK-like lytic activity, we contrasted the antitumor mechanism mediated
by rIL-12 with that of rIL-18. We showed here that rIL-12
administration greatly suppressed the in vivo growth of CL8-1 cells,
even in gld mice in which rIL-18 virtually had no antitumor
effects (Fig. 1B). In addition, cytolytic assay revealed
that rIL-12 administration failed to enhance the in vitro cytotoxicity
of hepatic MNCs harvested from perforin-deficient mice (Fig. 3). These
results indicate that IL-12 antitumor effects are mainly mediated
through perforin pathways, consistent with other recent reports that
suggest that the induction of perforin may be necessary for the
IL-12-enhanced cytolytic activity of lymphocytes (15, 16).
In contrast with IL-12, our results indicate that the antitumor effects
of IL-18 are mediated primarily through the Fas-FasL pathway. Although
both our in vitro and in vivo results consistently reveal the
importance of the Fas-FasL pathway in IL-18 antitumor effects, the role
of perforin in rIL-18-mediated effects differs when evaluated in vitro
and in vivo. Although the in vivo studies using gld mice
suggest a minor involvement of perforin-mediated killing in IL-18
antitumor effects, cytotoxicity was significantly reduced in assays
using lymphoid cells harvested from perforin gene-disrupted mice. This
is consistent with recent reports noting perforin-dependent
cytotoxicity of liver NK1+ T cells, which was
augmented in vitro by IL-18 administration (25). We
believe that these findings may be due to IFN- effects in vivo on
target cells induced by IL-18 administration but were not observed in
short-term in vitro cytotoxic assays. As previously reported in other
tumor lines (26, 27), IFN- treatment augmented
agonistic anti-Fas Ab-induced death of CL8-1 cells in our studies
(Fig. 6). rIL-18 administration induces Fas-mediated apoptosis both by
up-regulating FasL expression on NK cells and IFN--enhanced Fas
susceptibility of target cells. There are other possible explanations
for this difference between the in vivo and in vitro results.
Conventional CTLs may also participate in Fas-mediated apoptosis in
vivo. The in vitro cytotoxic assay used in our studies is dependent on
the NK activity of lymphoid cells but is not due to CTL activity. Our
recent studies evaluating gene-modified tumor cells to deliver IL-18
demonstrated that CD8+ T cells are involved in
IL-18 antitumor effects in animals bearing established tumor
(13). Thus, it is conceivable that a subset of T cells,
possibly sensitive to anti- asialo GM1 Ab treatment, may be
responsible for the difference observed in vitro and in vivo.
The antitumor effect associated with administration of rIL-18, but not rIL-12, is mediated by triggering Fas-dependent tumor apoptosis. The experiments performed here were primarily designed to study the role of rIL-18 in innate, but not adaptive, immune effector mechanisms. Although IL-18 does not directly drive Th1 development in contrast with IL-12 (6), our previous results (12) suggest that rIL-18 could indeed promote Th1 activity. Following rIL-18 administration and subsequent tumor cell apoptosis, enhanced Ag presentation to dendritic cells may increase and promote CTL generation. Apoptotic tumor cell death serves as source of Ag reported to be efficiently acquired by dendritic cells to promote class I-mediated CTL induction (28).
Some of the rIL-18 antitumor effects appear to be mediated by
nonimmunologic mechanisms, including antiangiogenesis. Coughlin et al.
have recently shown that the antitumor effects of IL-18 expressed
locally with IL-12 are mainly mediated by the antiangiogenic effects of
chemokines induced by IFN- (29). Detailed studies on
this issue are currently in progress in our laboratory using both
rIL-18 administration and IL-18 gene therapy. To date, our results are
consistent with the observation that IL-18 has antitumor effects
mediated by distinct mechanism when compared with that of IL-12
administration.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Medicine III, Osaka University Medical School, Osaka, Japan.
3 Address correspondence and reprint requests to Dr. Hideaki Tahara, Department of Surgery, University of Pittsburgh, 300 Kaufmann Building, 3471 Fifth Avenue, Pittsburgh, PA 15213. E-mail address:
4 Abbreviations used in this paper: FasL, Fas ligand; gld, generalized lymphoproliferative disease gene; lpr, lymphoproliferation gene; wt, wild type; MNC, mononuclear cells; i.d., intradermally; PI, propidium iodide; PKO, perforin knockout.
Received for publication January 13, 1999. Accepted for publication April 26, 1999.
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B. Immunity 7:571.[Medline]
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D. Arnold, C. Wasem, P. Juillard, P. Graber, I. Cima, C. Frutschi, S. Herren, S. Jakob, S. Alouani, C. Mueller, et al. IL-18-independent cytotoxic T lymphocyte activation and IFN-{gamma} production during experimental acute graft-versus-host disease Int. Immunol., May 1, 2002; 14(5): 503 - 511. [Abstract] [Full Text] [PDF]
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R. P. Singh, S.-i. Kashiwamura, P. Rao, H. Okamura, A. Mukherjee, and V. S. Chauhan The Role of IL-18 in Blood-Stage Immunity Against Murine Malaria Plasmodium yoelii265 and Plasmodium bergheiANKA J. Immunol., May 1, 2002; 168(9): 4674 - 4681. [Abstract] [Full Text] [PDF]
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R. Faggioni, R. C. Cattley, J. Guo, S. Flores, H. Brown, M. Qi, S. Yin, D. Hill, S. Scully, C. Chen, et al. IL-18-Binding Protein Protects Against Lipopolysaccharide- Induced Lethality and Prevents the Development of Fas/Fas Ligand-Mediated Models of Liver Disease in Mice J. Immunol., November 15, 2001; 167(10): 5913 - 5920. [Abstract] [Full Text] [PDF]
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C. Karnbach, M. R. Daws, E. C. Niemi, and M. C. Nakamura Immune Rejection of a Large Sarcoma Following Cyclophosphamide and IL-12 Treatment Requires Both NK and NK T Cells and Is Associated with the Induction of a Novel NK T Cell Population J. Immunol., September 1, 2001; 167(5): 2569 - 2576. [Abstract] [Full Text] [PDF]
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K. Shida, I. Shiratori, M. Matsumoto, Y. Fukumori, A. Matsuhisa, S. Kikkawa, S. Tsuji, H. Okamura, K. Toyoshima, and T. Seya An Alternative Form of IL-18 in Human Blood Plasma: Complex Formation with IgM Defined by Monoclonal Antibodies J. Immunol., June 1, 2001; 166(11): 6671 - 6679. [Abstract] [Full Text] [PDF]
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