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Department of Immunology and Medical Zoology and
Laboratory of Host Defenses, Institute for Advanced Medical Science, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan;
Department of Immunology, Juntendo University, Tokyo, Japan;
Howard Hughes Medical Institute, Department of Microbiology and Immunology, School of Medicine, Vanderbilt University, Nashville, TN 37232;
¶ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and
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Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-12 and IL-18 are potent proinflammatory cytokines (7, 8). IL-18 is produced as a biologically inactive precursor and, upon appropriate stimulation, becomes active by cleavage with caspase-1 or a caspase-1-like enzyme (8, 9, 10, 11). In some infectious diseases, IL-12 and/or IL-18, although frequently critical for expelling of the microbes, are critically important for the development of immunopathological changes in host target organs (7, 8). For example, LPS, a constituent of Gram-negative bacterial cell walls, can cause liver injury and lethal shock in humans and mice with an important role for IL-12 and IL-18 (12, 13). A recent study revealed that administration of neutralizing anti-IL-12 Abs protects mice from P. berghei-induced liver injury without affecting clearance of the parasite (5).
The Toll-like receptor (TLR)3 family represents a set of essential surface molecules for recognition of microbe-derived products to activate host innate immunity (14, 15). Following activation of TLRs by their corresponding ligands, the cytoplasmic domain of TLRs recruits a common adaptor molecule, myeloid differentiation factor 88 (MyD88), to activate a common signaling pathway, leading to production of cytokines including IL-12 (14, 15, 16). Although both bacterial and fungal components such as LPS and zymosan can activate this signaling pathway, it remains unclear whether microbial infection initiates activation of the TLR-MyD88 pathway in the host (15, 16, 17, 18, 19). Our recent study clearly demonstrated that Listeria monocytogenes infection of mice induces IL-12 production by a TLR-MyD88-dependent pathway (17). The role of the TLR-MyD88 signaling pathway for production of cytokines and liver injury caused by P. berghei is unknown.
In this study, we have investigated the mechanism by which P. berghei causes liver injury in mice. Although both IL-12 and IL-18 serum levels were elevated after infection, only IL-12-deficient mice were resistant to liver injury. Furthermore, MyD88-deficient mice were resistant to liver injury with production of IL-18 but not IL-12. Therefore, we conclude that protozoa can activate the TLR-MyD88 signaling pathway to induce pathological changes in the host. In addition, hepatic lymphocytes from P. berghei-infected mice gained the capacity to kill normal hepatocytes in a perforin-dependent and MHC-unrestricted manner. These findings suggest the involvement of an unusual killer-cell mechanism in P. berghei-induced liver injury.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 mice (6–8 wk old), C57BL/6 lpr/lpr mice (6–8 wk old), C3H/HeJ, and C3H/HeN (6–8 wk old) were purchased from SLC (Shizuoka, Japan). Female SCID mice (6–8 wk old) and BALB/c mice (6–8 wk old) were purchased from CLEA Japan (Osaka, Japan). Female perforin-deficient mice on a C57BL/6 background (10 wk old) were kindly provided by Dr. H. Yagita (Juntendo University, Tokyo, Japan). IL-18-deficient mice were backcrossed onto the C57BL/6 background and F8 (female, 6–8 wk old) animals were used in this study (20). IL-12-deficient mice on the C57BL/6 background were kindly provided by Dr. J. Magram (Hoffmann-La Roche, Nutley, NJ) and female mice (6–8 wk old) were used for this study (21). MyD88-deficient mice were backcrossed onto the BALB/c background and F8 (female, 6–8 wk old) animals were used (22). TLR6-deficient mice (8–11 wk old) were backcrossed with C57BL/6 mice and F2 animals were used (23). TLR2 and TLR4 double-knockout (DKO) mice onto the C57BL/6 129 background (9–11 wk old) were used for investigation. CD1d-deficient mice (6–8 wk old) have been described (24). All mice were kept under specific pathogen-free conditions.
Reagents
rIL-12 was a kind gift from Hayashibara (Okayama, Japan). Purified anti-Fas ligand (Fas L) mAb (MFL-1, hamster IgG) and murine Fas L-transfected cells (mFas L) were kindly provided by Dr. N. Kayagaki at Juntendo University (Tokyo, Japan) (25). Concanamycin A (CMA) was purchased from Wako (Osaka, Japan). The culture medium generally used was William’s medium (ICN Pharmaceuticals, Aurora, OH) containing 10% FCS, 100 U/ml penicillin, 100 µg/ml streptomycin, 50 µM of 2-ME, and 2 mM L-glutamine.
P. berghei-induced liver injury
Mice were i.p. inoculated with 106 erythrocytes parasitized with P. berghei (NK65) which was purchased from American Type Culture Collection (Manassas, VA). At various time points, liver specimens and serum were sampled for histological analysis and for measurement of the liver enzyme glutamic-pyruvic transaminase (GPT) and cytokine levels, respectively. Liver specimens were fixed in 3.5% formaldehyde in PBS and the slides were stained with H&E. Parasitemia was assessed by the microscopic examination of Giemsa-stained smears of tail blood. The percentage of parasitemia was calculated as follows: parasitemia (%) = [(number of infected erythrocytes)/(total number of erythrocytes counted)] x 100.
Assay for cytokines
IL-18 levels were measured by a commercially available ELISA kit (MBL, Nagoya, Japan). IL-12 p40 levels were also measured by a commercially available ELISA kit (Genzyme, Minneapolis, MN).
Preparation of hepatocytes and liver lymphocytes
Hepatocytes and liver lymphocytes were prepared from inoculated or noninoculated mice, as previously described (26, 27).
Ex vivo assay for hepatocytotoxicity
Hepatocytotoxicity of liver lymphocytes was determined by 4-h 51Cr release assays as previously described (26) with some modifications. In some experiments, liver lymphocytes were precultured with various doses of IL-12 overnight, or with 10 µg/ml anti-Fas L mAb or 20 nM CMA for 1 h at 37°C. Percent cytotoxicity was calculated as previously described (27). Spontaneous release of 51Cr by hepatocytes was <5% of the maximal release.
RT-PCR
Total RNA was extracted from hepatic lymphocytes isolated from
inoculated or noninoculated mice. RT-PCR for IL-12R
1, IL-12R2,
and -actin was performed as previously described
(27).
Statistics
All data are shown as the mean value of triplicate samples. Significance between the control group and a treated group was examined with the unpaired Student’s t test. Values of p < 0.05 were regarded as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because both IL-12 and IL-18 are potent proinflammatory cytokines
(7, 8, 27), we measured the serum concentration of IL-12
and IL-18 after infection of mice with P. berghei. IL-12 and
IL-18 levels peaked at day 4 and at day 6 after inoculation,
respectively (Fig. 1
, A and
B). IL-18 in the serum contained biologically active forms
because it induced IFN-
production by IL-18-sensitive cells (data
not shown).
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C). Histological analysis of the liver specimens of WT and
IL-18-deficient mice (Fig. 1D) revealed a mixture of focal
necrosis of hepatocytes and scattered apoptotic hepatocytes
characterized by condensed and fragmented nuclei, accompanied by dense
infiltration of mononuclear cells including lymphocytes. In sharp
contrast, GPT levels in P. berghei-infected IL-12-deficient
mice were similar to those of untreated animals. Histological analysis
demonstrated the absence of necrotic and apoptotic hepatocytes but the
presence of infiltrating lymphocytes. There were no differences of GPT
levels among uninfected WT, IL-12-deficient, and IL-18-deficient mice
(data not shown). Parasitemias in WT (Table I), IL-12-deficient, and IL-18-deficient
mice were comparable (data not shown). These results indicate that
IL-12, but not IL-18, is essential for P. berghei-induced
liver injury.
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To investigate whether the elevation of serum levels of IL-12
and/or IL-18 was mediated through the TLR-MyD88 signaling pathway, we
inoculated MyD88-deficient mice with P. berghei-infected
erythrocytes. The serum levels of IL-18 in MyD88-deficient mice were
almost the same as in WT mice, whereas those of IL-12 were dramatically
reduced (Fig. 2A). As expected
from the failure of IL-12-deficient mice to show Th1-dominant immune
response upon Bacille bilié de Calmette-Guérin infection, a
potent Th1 polarizer (20), MyD88-deficient mice showed
marked impairment in Th1 cell development (data not shown). Moreover,
like IL-12-deficient mice (Fig. 1D), MyD88-deficient mice
did not suffer from liver injury (Fig. 2, B and
C) (22) but showed equivalent infiltration of
lymphocytes in their livers compared with WT mice (Table I), indicating
the important role of IL-12 in P. berghei-induced liver
injury. Additionally, infected MyD88-deficient mice showed similar
mortality and parasitemia to P. berghei-infected WT mice
(Table I). Taken together, our findings indicate that MyD88 is
essential for serum accumulation of IL-12 but not IL-18. Therefore, we
conclude that P. berghei infection activates the TLR-MyD88
pathway to induce IL-12, which in turn results in liver injury.
However, despite our efforts to identify the TLR involved,
TLR(s)-deficient or mutant mice we tested showed production of
comparable levels of IL-12 and liver injury (Fig. 2, D–F, and data not shown), suggesting the
possible engagement of other TLRs and/or simultaneous engagement of
multiple TLRs with the complex components of P. berghei
protozoa.
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Animals treated with IL-12 do not show fatal pathological changes
(12). Therefore, we hypothesized that the liver injury
observed after infection of mice with P. berghei is caused
by the induction of effector molecules in response to IL-12 and other
factors. Furthermore, histological findings led us to investigate
whether infiltrating lymphocytes kill hepatocytes by the
perforin/granzyme and/or Fas/Fas L pathways, which can be activated by
IL-12 and IL-18, respectively (27, 28, 29). To address this
possibility, we examined whether functional Fas-deficient
lpr/lpr mice (30) were susceptible to liver
injury induced by P. berghei. lpr/lpr mice inoculated with
P. berghei-parasitized erythrocytes manifested almost the
same levels of liver injury with dense infiltration as in WT mice (Fig. 3, A and B)
suggesting that the Fas/Fas L pathway is not critical.
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, A and B). Thus, liver injury induced by
P. berghei infection occurs in a perforin-dependent Fas/Fas
L-independent manner. Unusual hepatocytotoxic lymphocytes accumulate in the liver of P. berghei-infected mice
To investigate the cellular and molecular mechanism of P.
berghei-induced liver injury, we conducted ex vivo
hepatocytotoxicity assays (26). Liver lymphocytes from
uninfected mice failed to kill hepatocytes from either infected or
uninfected mice (Fig. 4A).
However, liver lymphocytes from P. berghei-infected mice
showed cytotoxic activity against hepatocytes isolated from infected
mice (Fig. 4A). Surprisingly, hepatic lymphocytes from the
infected mice also attacked hepatocytes from uninfected mice (Fig. 4A). Furthermore, hepatic lymphocytes from the infected mice
killed hepatocytes from MHC-mismatched BALB/c mice (our unpublished
data), indicating that cytotoxicity occurs in an MHC-unrestricted
manner.
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). To provide further evidence that the
Fas/Fas L pathway of cell-mediated cytotoxicity is not required for the
liver injury induced by P. berghei, we performed
neutralization experiments with anti-Fas L mAb that completely
inhibit the killing action of Fas L-expressing cells against normal
hepatocytes (Fig. 4B). Anti-Fas L treatment had little
effect on the killing activity of hepatic lymphocytes from P.
berghei-infected mice against hepatocytes from either uninfected
or infected mice (Fig. 4A), indicating that the effector
lymphocytes killed hepatocytes in a Fas/Fas L-independent manner. In
separate experiments, we observed that the effector lymphocytes
precultured with control hamster IgG showed no reduction in this
cytotoxicity to both targets (data not shown). To confirm the
perforin-dependence of hepatocytotoxicity, we incubated liver
lymphocytes from the infected mice with CMA, an inhibitor for
maturation of perforin (27), and tested their
hepatocytotoxicity. Strong inhibitory effects of CMA for the cytotoxic
activities of hepatic lymphocytes from P. berghei-infected
mice were observed (Fig. 4A). CMA used in this study did not
affect the hepatocytotoxic action of mFas L (Fig. 4B). We
therefore conclude that P. berghei infection stimulates
hepatic lymphocytes to kill both autologous and allogeneic normal
hepatocytes in a perforin-dependent manner.
Freshly isolated hepatic lymphocytes from infected mice killed
hepatocytes ex vivo (Fig. 4A) and required continuous
stimulation with IL-12 in vitro to sustain their hepatocytotoxic
activity (Fig. 4C). However, IL-12-treated normal hepatic
lymphocytes did not kill hepatocytes from either uninfected or infected
mice (data not shown), suggesting that hepatic lymphocytes become
sensitive to IL-12 during infection of P. berghei. To
investigate this possibility, we evaluated mRNA expression of the
1 and 2 chains of IL-12R (7) in hepatic lymphocytes
before and after infection. Hepatic lymphocytes from uninfected mice
expressed only the 1 component, whereas those from infected mice
expressed both the 1 and 2 components (Fig. 4D). Thus,
hepatic lymphocytes increase their hepatocytotoxicity in response to
IL-12 because they have acquired increased levels of IL-12R after
infection.
CD1d-restricted NK T cells are not required for induction of liver injury by P. berghei
Finally, we analyzed characteristics of the unique
hepatocyte-killing lymphocytes that accumulate in the liver of P.
berghei-infected mice. SCID mice lacking T cells and B cells did
not suffer from this liver injury, indicating the requirement of T
cells in P. berghei-induced liver injury (Fig. 4E). Recently, it has been reported that CD1d-restricted NK
T cells can induce liver injury (32, 33, 34). For example,
administration of 
-galactosylceramide, a selective activator of
CD1d-restricted NK T cells (35), induced moderate liver
injury in WT mice but not in CD1d-deficient mice. To investigate the
possible involvement of CD1d-restricted NK T cells in the liver injury
induced by P. berghei infection, we inoculated
CD1d-deficient mice with parasitized erythrocytes. CD1d-deficient mice
were sensitive to the liver injury with similar histological changes as
WT mice (Fig. 4E) (data not shown). These results indicate
that T cells other than CD1d-restricted NK T cells, such as
conventional T cells and/or CD1d-unrestricted NK T cells, play an
essential role in this liver injury. Because conventional T cells
usually exert their cytotoxic action in an Ag-specific and
MHC-restricted manner (6), CD1d-unrestricted NK T cells
may be candidates for the effector cells in this liver injury.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and Fas L in the liver (28, 36). Liver
injury in this model is prevented by the administration of neutralizing
anti-IL-18 Abs (13) and is absent in IL-18-deficient
mice (37), indicating that IL-18 is essential for P.
acnes and LPS-induced liver injury. Furthermore, liver injury in
this model was dependent on induction of Fas L expression but
independent of perforin (11). Thus, IL-18 is required for
the induction of some types of liver injury. In contrast, the studies
described demonstrate that P. berghei-induced liver injury
is independent of IL-18 but dependent on endogenous IL-12 (Fig. 1, C and D), although both IL-18 and IL-12 levels in
the serum were augmented (Fig. 1, A and B).
IL-18-deficient mice were sensitive to P. berghei-induced
liver injury (Fig. 1, C and D). In addition,
administration of IL-18 into P. berghei-infected mice
resulted in no obvious changes in their liver disease (data not shown).
In contrast, IL-12 (Fig. 4C), but not IL-18 treatment (data
not shown), sustained or enhanced hepatocytotoxicity of hepatic
lymphocytes from the infected mice. Taken together, these studies
suggest that nonspecific liver injury can be caused by at least two
different mechanisms: 1) an IL-18-induced, Fas L-dependent mechanism
and 2) an IL-12-activated, perforin-dependent mechanism, as seen in
P. acnes/LPS-induced liver injury and P.
berghei-induced liver injury, respectively.
This is the first report demonstrating that a protozoan infection can
activate the TLR-MyD88 signaling pathway. TLR family members are
pattern-recognition receptors that are conserved among species from
insects to humans (14). To date, nine different TLRs have
been described (14, 15, 18). Recent studies have
revealed that some TLRs are critically important for recognition of
microbial pathogens by cells from innate immune systems (15, 18). In this study, we have shown that TLR-MyD88-mediated IL-12
production is responsible for perforin-dependent liver injury induced
by P. berghei infection (Fig. 3, 4). In contrast, IL-18 was
induced in a MyD88-independent manner after P. berghei
infection, which was also observed after L. monocytogenes
infection (17). However, as MyD88-deficient mice evaded
P. berghei-induced liver injury, IL-18 is not involved as a
causative factor for this liver injury.
Recently, it was reported that a protozoan glycosylphosphatidylinositol
anchor has the capacity to activate TLR2-mediated signaling
(38). Indeed, the glycosylphosphatidylinositol anchor in
P. falciparum can activate host innate immunoresponses
(39). The particular TLR(s) that is involved in IL-12
induction in P. berghei infection still remains unknown
(Fig. 2, D–F). After P. berghei
infection, not only WT mice, but also TLR6-deficient mice and
TLR4-mutant C3H/HeJ strain mice, (19, 40, 41) showed
obvious increases in IL-12 serum levels compared to uninfected mice
(Fig. 2, D and E) and liver injury (data not
shown), indicating that TLR6 or TLR4 is not solely responsible for the
induction of the liver injury. Furthermore, TLR2 and TLR4 DKO mice also
exhibited increases in IL-12 serum levels like WT mice (Fig. 2F) and liver injury (data not shown).
After infection with attenuated strains of malaria, host-derived IL-12
or exogenous IL-12 plays a critical role in its clearance (42, 43), suggesting that the TLR-MyD88 pathway is essential for host
defense against malaria. However, after infection with the fatal
strain P. berghei, IL-12 produced by the activation of
the TLR-MyD88 pathway causes liver injury but fails to clear the
protozoan parasite. Lymphocytes that can kill normal hepatocytes in a
MHC-unrestricted manner accumulated in the liver after P.
berghei infection. These lymphocytes expressed increased levels of
IL-12R (Fig. 4D) and were highly responsive to IL-12
stimulation, which may explain their unusual cytotoxic activities (Fig. 4, A and C). It has been reported that IL-12
up-regulates IL-12R expression on lymphocytes (44) and
that IL-12 up-regulates the cytotoxic activity of hepatic NK T cells
that constitutively express both 1 and 2 components of IL-12R in
vitro (28). Therefore, we investigated whether multiple
administrations of IL-12 can induce liver injury. This treatment
protocol failed to induce liver injury (45), suggesting
that a factor(s) other than IL-12 and/or cells other than
CD1d-restricted NK T cells are required to induce liver injury.
Additional studies will be required to identify this factor(s) and/or
effector cells. Splenocytes from the infected mice failed to kill
hepatocytes from either uninfected or infected mice (data not shown),
suggesting that these cells selectively accumulate in the liver of
P. berghei-infected mice. Interestingly, CD1d-deficient mice
were susceptible to P. berghei-induced liver injury (Fig. 4D), indicating that CD1d-restricted NK T cells are not
required for liver injury. This raises the possibility that
CD1d-unrestricted NK T cells accumulated in the liver become effector
cells after stimulation with IL-12 and possible other factors. This
unusual lymphocyte population may participate in infection-associated
tissue injuries that are now categorized in autoimmune disorders.
Further analysis of these cells will provide novel insights into
effector mechanisms underlying inflammatory disorders of the liver.
In summary, P. berghei infection induces activation of TLR-MyD88 signaling to produce IL-12, leading to liver injury in a perforin/granzyme-dependent manner.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kenji Nakanishi, Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. E-mail address: nakaken{at}hyo-med.ac.jp
3 Abbreviations used in this paper: TLR, Toll-like receptor; MyD88, myeloid differentiation factor 88; DKO, double-knockout mice; Fas L, Fas ligand; mFas L, murine Fas ligand; CMA, concanamycin A; GPT, glutamic-pyruvic transaminase; WT, wild type.
Received for publication March 12, 2001. Accepted for publication September 24, 2001.
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K. Adachi, H. Tsutsui, E. Seki, H. Nakano, K. Takeda, K. Okumura, L. Van Kaer, and K. Nakanishi Contribution of CD1d-unrestricted hepatic DX5+ NKT cells to liver injury in Plasmodium berghei-parasitized erythrocyte-injected mice Int. Immunol., June 1, 2004; 16(6): 787 - 798. [Abstract] [Full Text] [PDF]
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S. Pichyangkul, K. Yongvanitchit, U. Kum-arb, H. Hemmi, S. Akira, A. M. Krieg, D. G. Heppner, V. A. Stewart, H. Hasegawa, S. Looareesuwan, et al. Malaria Blood Stage Parasites Activate Human Plasmacytoid Dendritic Cells and Murine Dendritic Cells through a Toll-Like Receptor 9-Dependent Pathway J. Immunol., April 15, 2004; 172(8): 4926 - 4933. [Abstract] [Full Text] [PDF]
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C. A. Scanga, A. Bafica, C. G. Feng, A. W. Cheever, S. Hieny, and A. Sher MyD88-Deficient Mice Display a Profound Loss in Resistance to Mycobacterium tuberculosis Associated with Partially Impaired Th1 Cytokine and Nitric Oxide Synthase 2 Expression Infect. Immun., April 1, 2004; 72(4): 2400 - 2404. [Abstract] [Full Text] [PDF]
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T. J. Roberts, Y. Lin, P. M. Spence, L. Van Kaer, and R. R. Brutkiewicz CD1d1-Dependent Control of the Magnitude of an Acute Antiviral Immune Response J. Immunol., March 15, 2004; 172(6): 3454 - 3461. [Abstract] [Full Text] [PDF]
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M. A. Campos, M. Closel, E. P. Valente, J. E. Cardoso, S. Akira, J. I. Alvarez-Leite, C. Ropert, and R. T. Gazzinelli Impaired Production of Proinflammatory Cytokines and Host Resistance to Acute Infection with Trypanosoma cruzi in Mice Lacking Functional Myeloid Differentiation Factor 88 J. Immunol., February 1, 2004; 172(3): 1711 - 1718. [Abstract] [Full Text] [PDF]
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M. B. Drennan, D. Nicolle, V. J. F. Quesniaux, M. Jacobs, N. Allie, J. Mpagi, C. Fremond, H. Wagner, C. Kirschning, and B. Ryffel Toll-Like Receptor 2-Deficient Mice Succumb to Mycobacterium tuberculosis Infection Am. J. Pathol., January 1, 2004; 164(1): 49 - 57. [Abstract] [Full Text] [PDF]
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M. Skold and S. M. Behar Role of CD1d-Restricted NKT Cells in Microbial Immunity Infect. Immun., October 1, 2003; 71(10): 5447 - 5455. [Full Text] [PDF]
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J. A. Gold, M. Parsey, Y. Hoshino, S. Hoshino, A. Nolan, H. Yee, D. B. Tse, and M. D. Weiden CD40 Contributes to Lethality in Acute Sepsis: In Vivo Role for CD40 in Innate Immunity Infect. Immun., June 1, 2003; 71(6): 3521 - 3528. [Abstract] [Full Text] [PDF]
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H. Nakano, H. Tsutsui, M. Terada, K. Yasuda, K. Matsui, S. Yumikura-Futatsugi, K.-i. Yamanaka, H. Mizutani, T. Yamamura, and K. Nakanishi Persistent secretion of IL-18 in the skin contributes to IgE response in mice Int. Immunol., May 1, 2003; 15(5): 611 - 621. [Abstract] [Full Text] [PDF]
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E. Muraille, C. De Trez, M. Brait, P. De Baetselier, O. Leo, and Y. Carlier Genetically Resistant Mice Lacking MyD88-Adapter Protein Display a High Susceptibility to Leishmania major Infection Associated with a Polarized Th2 Response J. Immunol., April 15, 2003; 170(8): 4237 - 4241. [Abstract] [Full Text] [PDF]
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B. T. Edelson and E. R. Unanue MyD88-Dependent but Toll-Like Receptor 2-Independent Innate Immunity to Listeria: No Role for Either in Macrophage Listericidal Activity J. Immunol., October 1, 2002; 169(7): 3869 - 3875. [Abstract] [Full Text] [PDF]
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H. Konishi, H. Tsutsui, T. Murakami, S. Yumikura-Futatsugi, K.-i. Yamanaka, M. Tanaka, Y. Iwakura, N. Suzuki, K. Takeda, S. Akira, et al. IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions PNAS, August 20, 2002; 99(17): 11340 - 11345. [Abstract] [Full Text] [PDF]
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C. A. Scanga, J. Aliberti, D. Jankovic, F. Tilloy, S. Bennouna, E. Y. Denkers, R. Medzhitov, and A. Sher Cutting Edge: MyD88 Is Required for Resistance to Toxoplasma gondii Infection and Regulates Parasite-Induced IL-12 Production by Dendritic Cells J. Immunol., June 15, 2002; 168(12): 5997 - 6001. [Abstract] [Full Text] [PDF]
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), anti-Fas L Ab (
), or no substrate (
) for 1 h
before mixing with targets. Hepatic lymphocytes from uninfected mice
were precultured without any substrates (uninfected, 
). In separate
experiments, hepatic lymphocytes precultured with control Ab showed no
inhibition of hepatocytotoxicity (data not shown). Similar results were
obtained in three independent experiments. B, Labeled
target hepatocytes were incubated with mFas L, which had been treated
with or without CMA or anti-Fas L Ab as shown in A.
C and D, Hepatic lymphocytes from the
infected mice were incubated with various doses of IL-12 overnight and
their hepatocytotoxicity was determined by using normal hepatocytes
(C). Total RNA was extracted from hepatic lymphocytes
from uninfected (control) or infected mice (postinfection) and their
IL-12R