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/ß and IL-18 Synergistically Enhance IFN-
Gene Expression in Human T Cells1
*
Department of Virology, National Public Health Institute, Helsinki, Finland; and
Fujisaki Institute, Hayashibara Biochemical Laboratories, Okayama, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, a product of activated T and NK cells, has,
in addition to its direct antimicrobial activity, a major role in
activating cell-mediated immunity. Here we report that cytokines
secreted by influenza A virus-infected macrophages are able to induce
IFN- synthesis in human T cells. Influenza A virus-infected human
peripheral macrophages secreted IFN-
/ß, TNF-, IL-1ß, and a
recently identified cytokine, IL-18 (or IFN--inducing factor),
whereas the production of IL-12 was not detected. Supernatants
collected from virus-infected macrophages induced rapid IFN- mRNA
expression and protein production in T cells. This was down-regulated
by the addition of neutralizing anti-IFN-/ß Abs, whereas
neutralizing anti-IL-12 Abs had no effect on IFN- gene
expression. Exogenously added IFN-/ß also rapidly stimulated the
synthesis of IFN- mRNA in T cells independently of protein
synthesis. IL-18 synergized with IFN- to up-regulate IFN- gene
expression and protein production. The data suggest that IFN-/ß
and IL-18 produced by macrophages during virus infection may act
together to induce IFN- synthesis and, consequently, may play an
important role for both of these cytokines in the development of
Th1-type immune responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß is
one of the most abundant cytokines released by macrophages during viral
infections. The role of IFN-/ß as a direct antiviral substance has
been well documented, but its role as a significant immunoregulatory
molecule in T cell responses has also been suggested (3, 4).
IFN- is an important regulator of immune responses in vivo (5, 6, 7).
It is a product of activated T and NK cells and plays a critical role
in the host defense against microbial pathogens (8, 9). The expression
of the IFN- gene is strictly controlled at the transcriptional
level, the molecular mechanisms of which are presently not very well
understood (10, 11). IL-12 is a heterodimeric cytokine (12) produced
primarily by APCs, including monocytes, macrophages, and dendritic
cells, especially in bacterial infections (13, 14). It has a crucial
role in inducing IFN- production by T lymphocytes, and in the
generation of IFN--producing Th1 cells (15, 16, 17). Some other
costimulatory factors, such as TNF- and IL-1ß, may also be needed
for optimal IFN- production (18, 19). Data obtained from experiments
with IL-12 p40 knockout mice have suggested that alternative pathways
exist for IFN- induction (20). A novel cytokine, IL-18
(IFN--inducing factor
(IGIF)3), which shares
some but not all the biologic activities of IL-12, has been identified
and molecularly cloned from both mice and humans (21, 22, 23). Human IL-18
has been reported to induce IFN- and granulocyte/macrophage CSF
(GM-CSF) production in PBMC, decrease IL-10 production, and enhance NK
cell cytotoxicity (22).
In the present report we analyze the expression of IFN- in human T
lymphocytes during influenza A virus infection. We show that
IFN-/ß produced by virus-infected macrophages directly stimulates
IFN- production in T cells. Macrophages also respond to influenza A
virus infection by producing IL-18, which synergizes with IFN- to
stimulate IFN- gene expression and protein secretion. In our
experimental setting, macrophages infected with influenza A virus did
not produce IL-12. Thus, in influenza A virus infection,
macrophage-derived IFN-/ß and IL-18 may promote Th1-type immune
responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBMCs were isolated from freshly collected buffy coats of normal blood donors (Finnish Red Cross Blood Transfusion Service, Helsinki, Finland) by density gradient centrifugation using Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden). PBMCs were incubated in six-well plates (Falcon Multiwell, Becton Dickinson, Franklin Lakes, NJ) at 2 x 107 cells/well for 1 h at 37°C in serum-free RPMI 1640 medium supplemented with 20 mM HEPES, 2 mM glutamine, 0.6 µg/ml penicillin, and 60 µg/ml streptomycin. Adherent cells (monocytes) were thoroughly washed with PBS and grown in Macrophage-SFM medium (Life Technologies, Gaithersburg, MD) containing 10 ng/ml of GM-CSF (Leucomax, Schering-Plough, Innishannon, Ireland) and antibiotics. The medium was replaced every 2 days, and the cells were used in the experiments 1 to 2 wk after isolation. At this point, practically 100% of the cells were macrophages (24, 25), as determined by their initial CD14 expression, typical morphology, and lack of other cell types. T cells were further purified from nonadherent cells using nylon wool columns. Purified T cells were primarily stimulated with plate-bound anti-CD3 mAbs (26) and cultured in RPMI supplemented with 10% FCS (Integro, Zaandam, The Netherlands) and 100 IU/ml IL-2 (Chiron Corp., Emeryville, CA) for 6 days. Growing T cell cultures were expanded every 3 to 5 days with RPMI supplemented with FCS and IL-2, and used 2 wk after isolation. These cells are referred to as T cell blasts. As determined by flow cytometry, >99% of the cells were CD3 positive, consisting of CD4+ (30%) and CD8+ (70%) cells. In all the experiments, the T cells were removed from the IL-2-containing medium 16 h before stimulation.
Virus and infection
The stock of human pathogenic influenza virus A/Beijing/353/89 (H3N2), originating from the National Institute of Medical Research (London, U.K.), was grown in the allantoic cavities of 11-day-old embryonated hen eggs and stored at -70°C. The virus stock had a hemagglutination titer of 128 when a standard method was used (27). Macrophages grown to confluence in six-well plates were infected with the virus (1/10 dilution) in a 2-ml volume of Macrophage-SFM medium per well. After 1 h, the virus was removed, and the infected macrophages were washed with PBS and incubated further in RPMI with FCS. The cells or cell culture supernatants were collected at different times after infection. Allantoic fluid from uninfected embryonated eggs was used as a mock control. Both the virus and control stocks were endotoxin free, as tested by the Limulus assay. Macrophages or T cells from two to four donors were used in each experiment. In those experiments in which macrophage supernatants and T cells were used in a mixture, they always originated from the cells of the same donor.
Cytokines
Highly purified human leukocyte IFN- (13 x
106 IU/ml) was provided by Dr. Hannele
Tölö (Finnish Red Cross Blood Transfusion Service) and used
at 100 IU/ml, unless otherwise stated. Human IFN-ß (0.2 x
106 IU/ml) was obtained from Bioferon (Laupheim, Germany).
Human rIL-1ß, rIL-12, and rTNF- were obtained from R&D Systems
(Abingdon, U.K.) and used at 10, 5, and 10 ng/ml, respectively.
Escherichia coli-produced highly purified human rIL-18 (22)
was used at 10 ng/ml.
Antibodies
A 1/200 dilution of sheep antiserum specific for natural human
IFN-/ß (containing 450,000 neutralizing U/ml for IFN- and 3,000
neutralizing U/ml for IFN-ß) was used. This antiserum has previously
been described (28). Neutralizing anti-human IL-12 polyclonal Ab
was obtained from R&D Systems. The Ab concentration used (5 µg/ml)
was determined to be able to fully neutralize exogenously added IL-12
(1 ng/ml) to induce IFN- mRNA synthesis in T cells.
RNA isolation and analysis
RNA was isolated from pooled cell samples from different donors
by lysing cells in guanidinium thiocyanate and pelleting the RNA
through a 5.7-M CsCl2 cushion. Equal amounts (20 µg)
of total cellular RNA were size fractionated on a 1%
formaldehyde-agarose gel, transferred to a nylon membrane (Hybond,
Amersham, Aylesbury, U.K.), and hybridized with the cDNA probe encoding
human IFN- (29). Glyceraldehyde phosphate dehydrogenase (GAPDH) cDNA
probe, ß-actin cDNA probe, and ethidium bromide staining of ribosomal
RNA bands were used to ensure equal RNA loading. The probes were
labeled with [-32P]dCTP (3000 Ci/mmol; Amersham) using
a random primed DNA labeling kit (Boehringer Mannheim, Mannheim,
Germany). The membranes were hybridized under conditions of high
stringency (50% formamide, 5x SSPE, 5x Denhardt’s solution, and
0.5% SDS) at 42°C and washed twice at room temperature and once at
65°C in 1x SSC/0.1% SDS for 30 min each time. The filters were
exposed to Kodak AR X-OMAT film (Eastman Kodak, Rochester, NY) at
-70°C using an intensifying screen.
Assay for IFN-/ß bioactivity and cytokine ELISAs
The medium from the cell cultures was collected, pooled, and
stored in aliquots at -70°C until assayed. For the IFN-/ß
assay, the samples were dialyzed against acidic glycine buffer (pH 2)
to destroy possible IFN- and other cytokine activity, followed by
two dialyses against PBS and one against MEM. The IFN-/ß titers
were determined by means of a vesicular stomatitis virus plaque
reduction assay in the HEp2 cells (30). The biologic assay for
IFN-/ß was specified by the addition of neutralizing Abs against
IFN-/ß. The results are presented as international units per
milliliter using a standard IFN- preparation as a control. The
amounts of IFN-, TNF-, IL-1ß, and IL-12 in the culture
supernatants were measured by specific ELISA (R&D Systems). The
IL-18-specific ELISA assay was obtained from Hayashibara Biochemical
(Okayama, Japan) (31).
Western blotting analysis
The proteins were separated on 12% SDS-PAGE in accordance with the Laemmli buffer system (32), and then transferred electrophoretically onto Immobilon membranes (Millipore, Bedford, MA). Polyclonal rabbit anti-influenza A nucleoprotein antiserum (1/1000 dilution) (33) was allowed to bind in PBS containing 5% nonfat milk for 2 h at room temperature followed by secondary Ab binding with peroxidase-conjugated goat anti-rabbit IgG (Bio-Rad, Richmond, CA) for 30 min at room temperature. The protein bands were visualized by the ECL chemiluminescense system (Amersham). The protein sample concentrations were measured using a Bio-Rad protein assay kit.
Cycloheximide (CHX) treatment
For protein synthesis inhibition, T cells were incubated for 30 min in the presence of 10 µg/ml CHX (Sigma, St. Louis, MO). The concentration of CHX used was found previously to block protein synthesis in human blood mononuclear cells (33).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA and protein production in T cells
Our aim was to study, using human peripheral blood cells, whether
the cytokines produced by influenza A virus-infected macrophages are
responsible for inducing IFN- gene expression in T cells.
Macrophages were obtained from peripheral blood monocytes by culturing
them with GM-CSF as described previously (34, 35). Macrophages
originating from different blood donors were infected separately with
pathogenic influenza virus A/Beijing/353/89 (H3N2). After 1-h
infection, the unabsorbed virus was removed, and fresh medium was
added. The macrophages were cultured further, and samples of the
supernatant were collected at different times after virus infection.
The supernatants were then used to stimulate potential IFN-
production in T cell cultures originating from the same donor. After
3-h incubation, the majority of the cells were collected, and total
cellular RNA was prepared for Northern blot analysis. Elevated IFN-
mRNA levels were detected in T cells incubated with macrophage
supernatant collected at 6 h postinfection (Fig. 1
A, lane
4), and the maximum IFN- mRNA expression was seen
after stimulation with supernatants collected 16 and 24 h
postinfection (Fig. 1A, lanes 6 and
7). The remainder of the cells were incubated further
for 24 h, and IFN- secreted into the culture medium was
analyzed by ELISA. Supernatants collected at 16 or 24 h after
influenza A virus infection were equally effective in inducing IFN-
production in T cells (Fig. 1B). The data suggest
that cytokines or other soluble factors produced by virus-infected
macrophages may induce IFN- gene expression in T cells.
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A, lane
4), continued to accumulate up to 16 h, and
declined thereafter. Western blotting analysis showed that NP was
detectable at 2 h (Fig. 2B, lane 2),
apparently originating from the input virus, but started to accumulate
at 6 h postinfection and peaked at 16 h after infection.
Influenza A virus-infected T cells had kinetics very similar to those
of the macrophages. However, the amount of synthesized NP was much
smaller, as determined from mRNA and protein analysis (data not shown).
Human T cells infected with influenza A virus exhibited very low
IFN- mRNA expression at 2 h after infection, but this
disappeared totally thereafter. Very low levels of secreted IFN-
were observed in the T cell culture supernatant using a biologic assay
sensitive for this cytokine (data not shown).
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Several cytokines have previously been reported to enhance IFN-
production, including IFN-, TNF-, IL-1ß, IL-12, and IL-18 (18, 19, 21, 36, 37). To analyze whether these cytokines were produced in
our infection model, macrophages were infected with influenza virus as
described above. Supernatant samples were collected at different times
after infection and analyzed for the presence of various cytokines
using a biologic assay (IFN-/ß) or cytokine-specific ELISAs.
Influenza A virus-infected macrophages secreted IFN-/ß, TNF-,
and low amounts of IL-1ß (Fig. 3). In
addition, IL-18 was detected in the supernatant of the virus-infected
macrophages (Fig. 3). Expression of IL-12 was not observed at either
the mRNA (Northern blot) or the protein (ELISA) level (data not shown).
These results indicate that the possible cytokines involved in the
induction of IFN- synthesis in influenza A virus infection include
at least IFN-/ß, TNF-, IL-1ß, and IL-18.
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/ß produced by influenza A virus-infected macrophages
activates IFN- synthesis in T cells
To identify the cytokine(s) responsible for IFN- gene
expression, samples of the supernatants collected from the macrophages
infected with influenza A virus for 6 or 16 h were treated with
neutralizing anti-IFN-/ß or anti-IL-12 Abs for 30 min
before addition to the T cell cultures. The neutralizing capacity of
both these Abs was pretested to totally block the induction of IFN-
mRNA synthesis by IFN-/ß (1000 IU/ml) or IL-12 (1 ng/ml) in T
cells (data not shown). Treatment of the supernatants with
anti-IFN-/ß Abs significantly down-regulated IFN- mRNA
expression (Fig. 4, lanes
3 and 6), whereas the anti-IL-12 Abs
had no effect on IFN- gene expression (Fig. 4, lanes
4 and 7). This effect was seen with both
the 6 and 16 h supernatants, but not with the untreated
supernatants or the supernatants pretreated with anti-IL-12 Abs
(Fig. 4). T cells were also incubated with the supernatants pretreated
with neutralizing anti-TNF- or anti-IL-15 Abs or with normal
sheep serum, but none of these treatments affected the cell culture
supernatant-induced IFN- mRNA expression (data not shown).
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/ß in IFN- biosynthesis more closely,
T cells were directly incubated with two different concentrations (100
and 1000 IU/ml) of highly purified human leukocyte IFN-. The cells
were harvested 1, 3, and 6 h after IFN- stimulation and
analyzed by Northern blotting with an IFN--specific probe. The
kinetics of the IFN- mRNA synthesis were rapid. At 1 h, IFN-
mRNA levels were elevated with both doses of IFN- (Fig. 5, lanes 2 and
5), and maximum steady state mRNA levels were
detected 3 h after stimulation (Fig. 5, lanes 3 and
6). IFN- mRNA levels decreased thereafter, but
were still detectable at 6 h post stimulation. The induction of
IFN- production by IFN- was dose dependent. IFN- mRNA levels
increased with 1 IU/ml IFN- (data not shown), and maximum induction
occurred with 100 IU/ml (Fig. 5).
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gene by IFN-/ß is
independent of de novo protein synthesis, T cells were treated with CHX
for 30 min before the addition of IFN- or IFN-ß. The steady state
IFN- mRNA levels were analyzed 1 h after addition of these
cytokines. Both IFN- and IFN-ß induced the expression of the
IFN- gene in T cells (Fig. 6,
lanes 3 and 5). Treatment of T
cells with IFN- or IFN-ß in the presence of CHX resulted in the
induction of IFN- transcripts (Fig. 6, lanes 4 and
6), which was clearly more efficient than with CHX
alone (Fig. 6, lane 2). The data indicate
that the rapid induction of IFN- gene expression in T cells by type
I IFNs is direct and suggest that induction may not require ongoing
protein synthesis.
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/ß and IL-18 synergistically enhance IFN- mRNA
expression and protein production
When we compared the levels of IFN- mRNA induced in T cells by
the macrophage supernatant obtained from influenza A virus infection or
by purified IFN- preparation, we found that the former was a much
better inducer. This raises the possibility that different cytokines in
the supernatants of virus-infected macrophages function synergistically
in enhancing IFN- production in T cells. Therefore, we incubated T
cells in the presence of purified IL-1ß, IL-18, or TNF-, with
combinations of these with IFN-, as well as with IFN- alone and
analyzed the induction of IFN- gene expression and protein
production. IL-1ß or TNF- alone or combined with IFN- did not
markedly up-regulate IFN- mRNA synthesis (Fig. 7A, lanes 3,5, 6, and 8) or protein production
(Fig. 7B). IL-18 alone had no effect on IFN-
transcription (Fig. 7A, lane 4)
or protein production (Fig. 7B). Remarkably, the
combination of IFN- and IL-18 had a very strong synergistic effect
on both IFN- mRNA synthesis (Fig. 7A, lane
7) and protein production (Fig. 7B).
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synthesis
in our cell system. T cells responded to IL-12 by inducing IFN- mRNA
synthesis (Fig. 8, lane
3) and protein production (data not shown). Actually,
in our cell system IL-12 was a slightly more potent inducer of IFN-
mRNA synthesis than was IFN- (Fig. 8, lanes 2
and 3). However, IL-12 had no synergy with IFN- on
IFN- gene expression (Fig. 8, lane 5).
Our data, in accordance with the findings of previous experiments
conducted in a murine Th1 cell clone (21), show a very effective
synergy with IL-12 and IL-18 in IFN- production (Fig. 8, lane
7). These results demonstrate that the combination of
IFN-/ß and IL-18 and the combination of IL-12 and IL-18
efficiently induce IFN- production in human T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is one of the key
cytokines directing T cell immune responses toward Th1-type and
cell-mediated immunity (15). IFN- production in T lymphocytes and NK
cells can be triggered by contact with an Ag-presenting cell or target
cell, respectively. In addition, several monocyte/macrophage-derived
cytokines, including IL-1ß, IL-12, IL-18, and TNF-, can enhance
IFN- production (18, 19, 21, 37). Although experimental viral
infections in vivo (38) and in vitro (33) have been demonstrated to
induce IFN- production at early stages of infection, the molecular
mechanisms of IFN- gene regulation have remained unresolved. Studies
conducted in IL-12 knockout mice have shown that IL-12 is essential in
enhancing IFN- gene expression following endotoxin
administration (20).
To understand in more detail how IFN- gene expression is induced
during viral infections, we used an in vitro macrophage/T cell
infection model. Human leukocytes have previously been shown to be
susceptible to influenza A virus infection and to be able to produce
different cytokines during the infection (33, 39, 40). Human
macrophages were readily infected with influenza A virus.
Virus-infected T cells showed practically no enhancement of cytokine
gene expression (data not shown), whereas macrophages responded
actively by producing several different cytokines. The mechanisms by
which macrophages or T cells respond to intracellular pathogens by
producing different cytokines are not very well understood. The data
presented here suggest that macrophage-produced cytokines have a
significant biologic role in enhancing IFN- gene expression in T
cells. The cell culture supernatant of the influenza A virus-infected
macrophages efficiently enhanced IFN- gene expression. Determination
of cytokine levels in the cell culture supernatants revealed that
influenza A virus infection enhances IFN-/ß, TNF-, IL-1ß, and
IL-18 production in macrophages, whereas IL-12 was not induced at
either the mRNA or the protein level. This led us to assume that in the
absence of IL-12, other IFN--inducing molecules are involved. A
number of potential inducers could contribute to the induction of
IFN-, including IFN-, TNF-, IL-1ß (18, 19, 36), and IL-18
(21, 22). The addition of neutralizing anti-IFN-/ß Abs, but
not anti-IL-12 Abs, effectively inhibited IFN- gene expression
by the macrophage supernatant. This result clearly suggests that
IFN-/ß is able to induce IFN- gene expression in T cells. This
observation was further confirmed by the fact that purified IFN- was
able to enhance IFN- gene expression. Induction experiments
performed in the presence of CHX indicated that both IFN- and
IFN-ß can directly activate IFN- gene expression and suggest that
the induction of IFN- mRNA is at least partly independent of de novo
protein synthesis.
The IFN- mRNA signal and the production of IFN- protein induced
by the macrophage supernatant were greater than those observed with the
maximal dose of IFN-. Therefore, it was evident that some other
cytokine(s) was functioning together with IFN- to enhance IFN-
gene expression. Since several other cytokines in addition to
IFN-/ß were also produced by influenza A virus-infected
macrophages, we systematically tested their ability, alone or combined
with IFN-, to induce IFN- gene expression. The ability of IL-1ß
and TNF- to enhance IFN--induced IFN- gene expression was
minimal (Fig. 7
), even though it has previously been suggested that
IL-1ß and TNF- contribute to enhanced IFN- gene expression in
other cell systems (18, 19). IL-18, although alone a relatively weak
inducer of the IFN- gene in our T cell model, was very effective
when combined with IFN-. There was a >10-fold increase in IFN-
production when IFN- was combined with IL-18 (Fig. 7B). It is also likely that IFN-/ß and IL-18
synergistically enhance IFN- gene expression in virus-infected
macrophage/T cell cultures. The fact that both IFN-/ß and IL-18
are produced during virus infection in macrophages may indicate that
the combination of these cytokines is essential in directing the
immunity toward efficient Th1-type responses, which is often the case
in viral infections. However, before any general statements can be
made, systematic analyses of infections with other viruses will have to
be conducted.
It has been shown recently that a cellular serine protease, caspase-1
(or IL-1ß-converting enzyme) is involved in the proteolytic cleavage
of pro-IL-18 and subsequent secretion of the mature biologically active
form of IL-18 (41, 42). The activation of caspase-1 has been directly
linked to programmed cell death, apoptosis (43). Since influenza A
virus is capable of causing cell death by apoptotic mechanisms (44), it
is possible that the virus infection itself is responsible for the
presumed caspase-1 activation and IL-18 as well as for the IL-1ß
secretion from macrophages (Fig. 3). The IL-18 mRNA levels remained
relatively stable during influenza A infection (data not shown),
suggesting that there is an increase in the translation and/or
processing of IL-18 in response to viral infection. Further analysis of
the molecular mechanisms of IL-18 production during viral infection is
clearly necessary.
Interactions between a cytokine and its receptor lead to the activation
of several signaling molecules, including the family of STAT proteins
(45, 46). IFN- activates STAT1 and STAT2, which together with p48
protein (ISGF3 complex), bind to the promoter regions of genes that are
under the transcriptional control of IFN-. IL-12, in turn, induces
the tyrosine phosphorylation and DNA binding of STAT4 (47), which is
essential for IL-12 signaling, as shown by STAT4 gene knockout studies
(48, 49). However, it has recently been demonstrated by Cho et al. (50)
that STAT4 activation by IL-12 is not unique. IFN- is also able to
activate the tyrosine and serine phosphorylation and DNA binding of
STAT4 in human T lymphocytes and NK cells (50). Similarly, in our
experimental setting IFN- induced the tyrosine phosphorylation and
DNA binding activity of STAT4 in T cells (S. Matikainen, T. Sareneva,
and I. Julkunen, unpublished observations), suggesting that there is a
common molecular determinant of the overlapping functions of these two
cytokines, e.g., in the induction of IFN- gene transcription. In
addition, recently published results by Xu et al. (51) have
demonstrated that STAT4 has a role in the regulation of IFN- gene
expression.
IL-12, although not produced during influenza A infection by
macrophages, is one of the key cytokines regulating IFN- gene
expression. We analyzed the potential synergy among IFN-, IL-12, and
IL-18. It has previously been shown that IL-12 and IL-18 synergize very
strongly in enhancing IFN- gene expression (52). In our cell model
both IFN- and IL-12 synergistically enhanced IFN- mRNA expression
in combination with IL-18 (Fig. 8). The fact that IFN- and IL-12 did
not exhibit any synergy suggests that these cytokines can perhaps
substitute for each other in the regulation of IFN- gene expression.
These observations raise interesting biologic consequences. In viral
infections IFNs and IL-18 are produced, whereas the production of IL-12
may be limited. However, in bacterial infections IL-12 and IL-18
(53, 54, 55) are produced, but IFN- is not. As a consequence, IFN-
production in viral infections may be a significant factor leading to
efficient Th1-type immune responses. Recently, the role of IFN- as a
Th1-type cytokine was supported by Rogge et al. (56), who demonstrated
the up-regulation of IL-12R ß2-chain synthesis by IL-12 and IFN-
in human T cells and that both of these cytokines have important roles
in the functional activity and development of T cells.
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Acknowledgments |
|---|
, Dr. Matti
Kaartinen for the anti-CD3 Abs, and Ms. Marika Yliselä, Ms.
Mari Tapaninen, and Ms. Valma Mäkinen for their technical
assistance. |
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Timo Sareneva, Department of Virology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail address:
3 Abbreviations used in this paper: IGIF, IFN--inducing factor; GM-CSF, granulocyte/macrophage-CSF; CHX, cycloheximide; NP, nucleoprotein.
Received for publication November 11, 1997. Accepted for publication February 10, 1998.
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 T. de Boer, J. T. van Dissel, T. W. J. Kuijpers, G. F. Rimmelzwaan, F. P. Kroon, and T. H. M. Ottenhoff Influenza Virus Vaccination Induces Interleukin-12/23 Receptor {beta}1 (IL-12/23R{beta}1)-Independent Production of Gamma Interferon (IFN-{gamma}) and Humoral Immunity in Patients with Genetic Deficiencies in IL-12/23R{beta}1 or IFN-{gamma} Receptor I Clin. Vaccine Immunol., August 1, 2008; 15(8): 1171 - 1175. [Abstract] [Full Text] [PDF]
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M. Feld, V. M. Shpacovitch, C. Ehrhardt, C. Kerkhoff, M. D. Hollenberg, N. Vergnolle, S. Ludwig, and M. Steinhoff Agonists of Proteinase-Activated Receptor-2 Enhance IFN-{gamma}-Inducible Effects on Human Monocytes: Role in Influenza A Infection J. Immunol., May 15, 2008; 180(10): 6903 - 6910. [Abstract] [Full Text] [PDF]
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A. M. Davis, K. A. Hagan, L. A. Matthews, G. Bajwa, M. A. Gill, M. Gale Jr., and J. D. Farrar Blockade of Virus Infection by Human CD4+ T Cells via a Cytokine Relay Network J. Immunol., May 15, 2008; 180(10): 6923 - 6932. [Abstract] [Full Text] [PDF]
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V. Athie-Morales, G. M. O'Connor, and C. M. Gardiner Activation of Human NK Cells by the Bacterial Pathogen-Associated Molecular Pattern Muramyl Dipeptide J. Immunol., March 15, 2008; 180(6): 4082 - 4089. [Abstract] [Full Text] [PDF]
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J. Rintahaka, D. Wiik, P. E. Kovanen, H. Alenius, and S. Matikainen Cytosolic Antiviral RNA Recognition Pathway Activates Caspases 1 and 3 J. Immunol., February 1, 2008; 180(3): 1749 - 1757. [Abstract] [Full Text] [PDF]
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J. Pirhonen, J. Siren, I. Julkunen, and S. Matikainen IFN-{alpha} regulates Toll-like receptor-mediated IL-27 gene expression in human macrophages J. Leukoc. Biol., November 1, 2007; 82(5): 1185 - 1192. [Abstract] [Full Text] [PDF]
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H. J. Ramos, A. M. Davis, T. C. George, and J. D. Farrar IFN-{alpha} Is Not Sufficient to Drive Th1 Development Due to Lack of Stable T-bet Expression J. Immunol., September 15, 2007; 179(6): 3792 - 3803. [Abstract] [Full Text] [PDF]
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 M. J. Carter A rationale for using steroids in the treatment of severe cases of H5N1 avian influenza J. Med. Microbiol., July 1, 2007; 56(7): 875 - 883. [Abstract] [Full Text] [PDF]
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A. A. Byrnes, D.-Y. Li, K. Park, D. Thompson, C. Mocilnikar, P. Mohan, J. P. Molleston, M. Narkewicz, H. Zhou, S. F. Wolf, et al. Modulation of the IL-12/IFN-{gamma} axis by IFN-{alpha} therapy for hepatitis C J. Leukoc. Biol., March 1, 2007; 81(3): 825 - 834. [Abstract] [Full Text] [PDF]
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D. O. Co, L. H. Hogan, J. Karman, E. Heninger, S. Vang, K. Wells, Y. Kawaoka, and M. Sandor Interactions between T Cells Responding to Concurrent Mycobacterial and Influenza Infections J. Immunol., December 15, 2006; 177(12): 8456 - 8465. [Abstract] [Full Text] [PDF]
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 E. K.-W. Hui, D. F. Smee, M.-H. Wong, and D. P. Nayak Mutations in Influenza Virus M1 CCHH, the Putative Zinc Finger Motif, Cause Attenuation in Mice and Protect Mice against Lethal Influenza Virus Infection. J. Virol., June 1, 2006; 80(12): 5697 - 5707. [Abstract] [Full Text] [PDF]
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T. E. Pietila, V. Veckman, P. Kyllonen, K. Lahteenmaki, T. K. Korhonen, and I. Julkunen Activation, cytokine production, and intracellular survival of bacteria in Salmonella-infected human monocyte-derived macrophages and dendritic cells J. Leukoc. Biol., October 1, 2005; 78(4): 909 - 920. [Abstract] [Full Text] [PDF]
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P. Osterlund, V. Veckman, J. Siren, K. M. Klucher, J. Hiscott, S. Matikainen, and I. Julkunen Gene Expression and Antiviral Activity of Alpha/Beta Interferons and Interleukin-29 in Virus-Infected Human Myeloid Dendritic Cells J. Virol., August 1, 2005; 79(15): 9608 - 9617. [Abstract] [Full Text] [PDF]
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J. Tissari, J. Siren, S. Meri, I. Julkunen, and S. Matikainen IFN-{alpha} Enhances TLR3-Mediated Antiviral Cytokine Expression in Human Endothelial and Epithelial Cells by Up-Regulating TLR3 Expression J. Immunol., April 1, 2005; 174(7): 4289 - 4294. [Abstract] [Full Text] [PDF]
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J. Siren, J. Pirhonen, I. Julkunen, and S. Matikainen IFN-{alpha} Regulates TLR-Dependent Gene Expression of IFN-{alpha}, IFN-{beta}, IL-28, and IL-29 J. Immunol., February 15, 2005; 174(4): 1932 - 1937. [Abstract] [Full Text] [PDF]
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 J. Stasakova, B. Ferko, C. Kittel, S. Sereinig, J. Romanova, H. Katinger, and A. Egorov Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1{beta} and 18 J. Gen. Virol., January 1, 2005; 86(1): 185 - 195. [Abstract] [Full Text] [PDF]
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M. E. Persky, K. M. Murphy, and J. D. Farrar IL-12, but Not IFN-{alpha}, Promotes STAT4 Activation and Th1 Development in Murine CD4+ T Cells Expressing a Chimeric Murine/Human Stat2 Gene J. Immunol., January 1, 2005; 174(1): 294 - 301. [Abstract] [Full Text] [PDF]
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J. Siren, T. Sareneva, J. Pirhonen, M. Strengell, V. Veckman, I. Julkunen, and S. Matikainen Cytokine and contact-dependent activation of natural killer cells by influenza A or Sendai virus-infected macrophages J. Gen. Virol., August 1, 2004; 85(8): 2357 - 2364. [Abstract] [Full Text] [PDF]
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M. Strengell, I. Julkunen, and S. Matikainen IFN-{alpha} regulates IL-21 and IL-21R expression in human NK and T cells J. Leukoc. Biol., August 1, 2004; 76(2): 416 - 422. [Abstract] [Full Text] [PDF]
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 L. A. Rosenthal, L. D. Mikus, A. Tuffaha, A. G. Mosser, R. L. Sorkness, and R. F. Lemanske Jr. Attenuated Innate Mechanisms of Interferon-{gamma} Production in Rats Susceptible to Postviral Airway Dysfunction Am. J. Respir. Cell Mol. Biol., May 1, 2004; 30(5): 702 - 709. [Abstract] [Full Text] [PDF]
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 B. J. Marsland, N. L. Harris, M. Camberis, M. Kopf, S. M. Hook, and G. Le Gros Bystander suppression of allergic airway inflammation by lung resident memory CD8+ T cells PNAS, April 20, 2004; 101(16): 6116 - 6121. [Abstract] [Full Text] [PDF]
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V. Athie-Morales, H. H. Smits, D. A. Cantrell, and C. M. U. Hilkens Sustained IL-12 Signaling Is Required for Th1 Development J. Immunol., January 1, 2004; 172(1): 61 - 69. [Abstract] [Full Text] [PDF]
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L. Malmgaard and S. R. Paludan Interferon (IFN)-{alpha}/{beta}, interleukin (IL)-12 and IL-18 coordinately induce production of IFN-{gamma} during infection with herpes simplex virus type 2 J. Gen. Virol., September 1, 2003; 84(9): 2497 - 2500. [Abstract] [Full Text] [PDF]
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M. M. Gherardi, J. C. Ramirez, and M. Esteban IL-12 and IL-18 act in synergy to clear vaccinia virus infection: involvement of innate and adaptive components of the immune system J. Gen. Virol., August 1, 2003; 84(8): 1961 - 1972. [Abstract] [Full Text] [PDF]
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M. Strengell, S. Matikainen, J. Siren, A. Lehtonen, D. Foster, I. Julkunen, and T. Sareneva IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-{gamma} Production in Human NK and T Cells J. Immunol., June 1, 2003; 170(11): 5464 - 5469. [Abstract] [Full Text] [PDF]
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T. Kambayashi, E. Assarsson, A. E. Lukacher, H.-G. Ljunggren, and P. E. Jensen Memory CD8+ T Cells Provide an Early Source of IFN-{gamma} J. Immunol., March 1, 2003; 170(5): 2399 - 2408. [Abstract] [Full Text] [PDF]
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J. A. Gracie, S. E. Robertson, and I. B. McInnes Interleukin-18 J. Leukoc. Biol., February 1, 2003; 73(2): 213 - 224. [Abstract] [Full Text] [PDF]
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R. Lande, E. Giacomini, T. Grassi, M. E. Remoli, E. Iona, M. Miettinen, I. Julkunen, and E. M. Coccia IFN-{alpha}{beta} Released by Mycobacterium tuberculosis-Infected Human Dendritic Cells Induces the Expression of CXCL10: Selective Recruitment of NK and Activated T Cells J. Immunol., February 1, 2003; 170(3): 1174 - 1182. [Abstract] [Full Text] [PDF]
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J. Pirhonen, S. Matikainen, and I. Julkunen Regulation of Virus-Induced IL-12 and IL-23 Expression in Human Macrophages J. Immunol., November 15, 2002; 169(10): 5673 - 5678. [Abstract] [Full Text] [PDF]
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G. C. Pien, K. B. Nguyen, L. Malmgaard, A. R. Satoskar, and C. A. Biron A Unique Mechanism for Innate Cytokine Promotion of T Cell Responses to Viral Infections J. Immunol., November 15, 2002; 169(10): 5827 - 5837. [Abstract] [Full Text] [PDF]
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M. Strengell, T. Sareneva, D. Foster, I. Julkunen, and S. Matikainen IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response J. Immunol., October 1, 2002; 169(7): 3600 - 3605. [Abstract] [Full Text] [PDF]
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 K. B. Nguyen, W. T. Watford, R. Salomon, S. R. Hofmann, G. C. Pien, A. Morinobu, M. Gadina, J. J. O'Shea, and C. A. Biron Critical Role for STAT4 Activation by Type 1 Interferons in the Interferon-gamma Response to Viral Infection Science, September 20, 2002; 297(5589): 2063 - 2066. [Abstract] [Full Text] [PDF]
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M. A. Freudenberg, T. Merlin, C. Kalis, Y. Chvatchko, H. Stubig, and C. Galanos Cutting Edge: A Murine, IL-12-Independent Pathway of IFN-{gamma} Induction by Gram-Negative Bacteria Based on STAT4 Activation by Type I IFN and IL-18 Signaling J. Immunol., August 15, 2002; 169(4): 1665 - 1668. [Abstract] [Full Text] [PDF]
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 T. Luft, M. Jefford, P. Luetjens, T. Toy, H. Hochrein, K.-A. Masterman, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E2 regulates the migratory capacity of specific DC subsets Blood, July 30, 2002; 100(4): 1362 - 1372. [Abstract] [Full Text] [PDF]
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A. Ariel, D. Novick, M. Rubinstein, C. A. Dinarello, O. Lider, and R. Hershkoviz IL-12 and IL-18 induce MAP kinase-dependent adhesion of T cells to extracellular matrix components J. Leukoc. Biol., July 1, 2002; 72(1): 192 - 198. [Abstract] [Full Text] [PDF]
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Z. Trobonjaca, A. Kroger, D. Stober, F. Leithauser, P. Moller, H. Hauser, R. Schirmbeck, and J. Reimann Activating Immunity in the Liver. II. IFN-{beta} Attenuates NK Cell-Dependent Liver Injury Triggered by Liver NKT Cell Activation J. Immunol., April 15, 2002; 168(8): 3763 - 3770. [Abstract] [Full Text] [PDF]
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D. L. Brassard, M. J. Grace, and R. W. Bordens Interferon-{alpha} as an immunotherapeutic protein J. Leukoc. Biol., April 1, 2002; 71(4): 565 - 581. [Abstract] [Full Text] [PDF]
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 T. Luft, P. Luetjens, H. Hochrein, T. Toy, K.-A. Masterman, M. Rizkalla, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky IFN-{alpha} enhances CD40 ligand-mediated activation of immature monocyte-derived dendritic cells Int. Immunol., April 1, 2002; 14(4): 367 - 380. [Abstract] [Full Text] [PDF]
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H. H. Smits, E. C. de Jong, J. H. N. Schuitemaker, T. B. H. Geijtenbeek, Y. van Kooyk, M. L. Kapsenberg, and E. A. Wierenga Intercellular Adhesion Molecule-1/LFA-1 Ligation Favors Human Th1 Development J. Immunol., February 15, 2002; 168(4): 1710 - 1716. [Abstract] [Full Text] [PDF]
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 V M Salvati, T T MacDonald, M Bajaj-Elliott, M Borrelli, A Staiano, S Auricchio, R Troncone, and G Monteleone Interleukin 18 and associated markers of T helper cell type 1 activity in coeliac disease Gut, February 1, 2002; 50(2): 186 - 190. [Abstract] [Full Text] [PDF]
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J. A. Jordan, R.-F. Guo, E. C. Yun, V. Sarma, R. L. Warner, L. D. Crouch, G. Senaldi, T. R. Ulich, and P. A. Ward Role of IL-18 in Acute Lung Inflammation J. Immunol., December 15, 2001; 167(12): 7060 - 7068. [Abstract] [Full Text] [PDF]
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A. Gigliotti Rothfuchs, D. Gigliotti, K. Palmblad, U. Andersson, H. Wigzell, and M. E. Rottenberg IFN-{alpha}{beta}-Dependent, IFN-{gamma} Secretion by Bone Marrow-Derived Macrophages Controls an Intracellular Bacterial Infection J. Immunol., December 1, 2001; 167(11): 6453 - 6461. [Abstract] [Full Text] [PDF]
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B. Ferko, J. Stasakova, S. Sereinig, J. Romanova, D. Katinger, B. Niebler, H. Katinger, and A. Egorov Hyperattenuated Recombinant Influenza A Virus Nonstructural-Protein-Encoding Vectors Induce Human Immunodeficiency Virus Type 1 Nef-Specific Systemic and Mucosal Immune Responses in Mice J. Virol., October 1, 2001; 75(19): 8899 - 8908. [Abstract] [Full Text] [PDF]
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E. Giacomini, E. Iona, L. Ferroni, M. Miettinen, L. Fattorini, G. Orefici, I. Julkunen, and E. M. Coccia Infection of Human Macrophages and Dendritic Cells with Mycobacterium tuberculosis Induces a Differential Cytokine Gene Expression That Modulates T Cell Response J. Immunol., June 15, 2001; 166(12): 7033 - 7041. [Abstract] [Full Text] [PDF]
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 T. H. Mogensen and S. R. Paludan Molecular Pathways in Virus-Induced Cytokine Production Microbiol. Mol. Biol. Rev., March 1, 2001; 65(1): 131 - 150. [Abstract] [Full Text] [PDF]
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L. D. Mikus, L. A. Rosenthal, R. L. Sorkness, and R. F. Lemanske Jr. Reduced Interferon-{gamma} Secretion by Natural Killer Cells from Rats Susceptible to Postviral Chronic Airway Dysfunction Am. J. Respir. Cell Mol. Biol., January 1, 2001; 24(1): 74 - 82. [Abstract] [Full Text]
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L. Malmgaard, S. R. Paludan, S. C. Mogensen, and S. Ellermann-Eriksen Herpes simplex virus type 2 induces secretion of IL-12 by macrophages through a mechanism involving NF-{kappa}B J. Gen. Virol., December 1, 2000; 81(12): 3011 - 3020. [Abstract] [Full Text]
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G. C. Pien, A. R. Satoskar, K. Takeda, S. Akira, and C. A. Biron Cutting Edge: Selective IL-18 Requirements for Induction of Compartmental IFN-{gamma} Responses During Viral Infection J. Immunol., November 1, 2000; 165(9): 4787 - 4791. [Abstract] [Full Text] [PDF]
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S. Riffault, C. Carrat, G. Milon, B. Charley, and J. H. Colle Transient IFN-{gamma} synthesis in the lymph node draining a dermal site loaded with UV-irradiated herpes simplex virus type 1: an NK- and CD3-dependent process regulated by IL-12 but not by IFN-{alpha}/{beta} J. Gen. Virol., October 1, 2000; 81(10): 2365 - 2373. [Abstract] [Full Text]
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S. Oh and M. C. Eichelberger Polarization of Allogeneic T-Cell Responses by Influenza Virus-Infected Dendritic Cells J. Virol., September 1, 2000; 74(17): 7738 - 7744. [Abstract] [Full Text]
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T. Sareneva, I. Julkunen, and S. Matikainen IFN-{alpha} and IL-12 Induce IL-18 Receptor Gene Expression in Human NK and T Cells J. Immunol., August 15, 2000; 165(4): 1933 - 1938. [Abstract] [Full Text] [PDF]
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 C. E. Verhagen, T. de Boer, H. H. Smits, F. A.W. Verreck, E. A. Wierenga, M. Kurimoto, D. A. Lammas, D. S. Kumararatne, O. Sanal, F. P. Kroon, et al. Residual Type 1 Immunity in Patients Genetically Deficient for Interleukin 12 Receptor {beta}1 (IL-12R{beta}1): Evidence for an IL-12R{beta}1-independent Pathway of IL-12 Responsiveness in Human T Cells J. Exp. Med., August 14, 2000; 192(4): 517 - 528. [Abstract] [Full Text] [PDF]
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 C.-H. Song, H.-J. Kim, J.-K. Park, J.-H. Lim, U.-O. Kim, J.-S. Kim, T.-H. Paik, K.-J. Kim, J.-W. Suhr, and E.-K. Jo Depressed Interleukin-12 (IL-12), but not IL-18, Production in Response to a 30- or 32-Kilodalton Mycobacterial Antigen in Patients with Active Pulmonary Tuberculosis Infect. Immun., August 1, 2000; 68(8): 4477 - 4484. [Abstract] [Full Text] [PDF]
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L. A. Pinto, V. Blazevic, B. K. Patterson, C. Mac Trubey, M. J. Dolan, and G. M. Shearer Inhibition of Human Immunodeficiency Virus Type 1 Replication prior to Reverse Transcription by Influenza Virus Stimulation J. Virol., May 15, 2000; 74(10): 4505 - 4511. [Abstract] [Full Text]
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M. Miettinen, A. Lehtonen, I. Julkunen, and S. Matikainen Lactobacilli and Streptococci Activate NF-{kappa}B and STAT Signaling Pathways in Human Macrophages J. Immunol., April 1, 2000; 164(7): 3733 - 3740. [Abstract] [Full Text] [PDF]
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A. Sing, T. Merlin, H.-P. Knopf, P. J. Nielsen, H. Loppnow, C. Galanos, and M. A. Freudenberg Bacterial Induction of Beta Interferon in Mice Is a Function of the Lipopolysaccharide Component Infect. Immun., March 1, 2000; 68(3): 1600 - 1607. [Abstract] [Full Text] [PDF]
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 G. Herbein and W. A. O'brien Tumor Necrosis Factor (TNF)-{alpha} and TNF Receptors in Viral Pathogenesis Experimental Biology and Medicine, March 1, 2000; 223(3): 241 - 257. [Abstract] [Full Text]
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L. D. Giavedoni, M. C. Velasquillo, L. M. Parodi, G. B. Hubbard, and V. L. Hodara Cytokine Expression, Natural Killer Cell Activation, and Phenotypic Changes in Lymphoid Cells from Rhesus Macaques during Acute Infection with Pathogenic Simian Immunodeficiency Virus J. Virol., February 15, 2000; 74(4): 1648 - 1657. [Abstract] [Full Text]
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A. Paananen, R. Mikkola, T. Sareneva, S. Matikainen, M. Andersson, I. Julkunen, M. S. Salkinoja-Salonen, and T. Timonen Inhibition of Human NK Cell Function by Valinomycin, a Toxin from Streptomyces griseus in Indoor Air Infect. Immun., January 1, 2000; 68(1): 165 - 169. [Abstract] [Full Text] [PDF]
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 K. Fassbender, O. Mielke, T. Bertsch, F. Muehlhauser, M. Hennerici, M. Kurimoto, and S. Rossol Interferon-{gamma}-inducing factor (IL-18) and interferon-{gamma} in inflammatory CNS diseases Neurology, September 1, 1999; 53(5): 1104 - 1104. [Abstract] [Full Text] [PDF]
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J. Pirhonen, T. Sareneva, M. Kurimoto, I. Julkunen, and S. Matikainen Virus Infection Activates IL-1{beta} and IL-18 Production in Human Macrophages by a Caspase-1-Dependent Pathway J. Immunol., June 15, 1999; 162(12): 7322 - 7329. [Abstract] [Full Text] [PDF]
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V. E. Garcia, K. Uyemura, P. A. Sieling, M. T. Ochoa, C. T. Morita, H. Okamura, M. Kurimoto, T. H. Rea, and R. L. Modlin IL-18 Promotes Type 1 Cytokine Production from NK Cells and T Cells in Human Intracellular Infection J. Immunol., May 15, 1999; 162(10): 6114 - 6121. [Abstract] [Full Text] [PDF]
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L. P. Cousens, R. Peterson, S. Hsu, A. Dorner, J. D. Altman, R. Ahmed, and C. A. Biron Two Roads Diverged: Interferon alpha /beta - and Interleukin 12-mediated Pathways in Promoting T Cell Interferon gamma Responses during Viral Infection J. Exp. Med., April 19, 1999; 189(8): 1315 - 1328. [Abstract] [Full Text] [PDF]
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S. Matikainen, T. Sareneva, T. Ronni, A. Lehtonen, P. J. Koskinen, and I. Julkunen Interferon-alpha Activates Multiple STAT Proteins and Upregulates Proliferation-Associated IL-2Ralpha , c-myc, and pim-1 Genes in Human T Cells Blood, March 15, 1999; 93(6): 1980 - 1991. [Abstract] [Full Text] [PDF]
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M. Miettinen, S. Matikainen, J. Vuopio-Varkila, J. Pirhonen, K. Varkila, M. Kurimoto, and I. Julkunen Lactobacilli and Streptococci Induce Interleukin-12 (IL-12), IL-18, and Gamma Interferon Production in Human Peripheral Blood Mononuclear Cells Infect. Immun., December 1, 1998; 66(12): 6058 - 6062. [Abstract] [Full Text] [PDF]
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