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, IL-12, and IFN-
, and Induction of IL-10
*
Department of Experimental Medicine, University of Perugia, Perugia, Italy; and
Ludwig Institute for Cancer Research, Brussels, Belgium
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-12, and IFN-
,
as well as the induction of the anti-inflammatory cytokine IL-10.
Sustained levels of IL-9-specific transcripts could be detected in the
spleens of mice recovering from sublethal P. aeruginosa
infection. Therefore, IL-9 may be protective in septic shock via a
rather unique mechanism involving a complex modulation of inflammatory
and anti-inflammatory mediators. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1, IL-6, IL-12, and IFN-
(5). IL-12, in concert with TNF- or B7 costimulation,
can further act as a potent inducer of IFN- production by T and NK
cells (6, 7, 8). The central role of proinflammatory
cytokines in the pathogenesis of endotoxic shock is underlined by the
occurrence of high levels of circulating cytokines in both humans and
experimental animals during endotoxemia (9). During the course of septic shock, triggering of regulatory mechanisms may oppose macrophage activation (10), thus alleviating an overwhelming, dysregulated inflammatory response that contributes to pathology and potentially death in the host. This concept is supported by a large body of evidence showing the ability of anti-cytokine maneuvers to improve outcome in experimental challenge with LPS or Gram-negative bacteria. Administration of neutralizing anti-cytokine Abs (11, 12) or of IL-1R antagonist (13) or gene targeting of proinflammatory cytokines (14) or cytokine receptors (15, 16) can diminish lethality in experimental endotoxemia.
Therapeutic effects in experimental septic shock syndromes are also
achieved by the administration of recombinant cytokines with
macrophage-deactivating properties. IL-10 can act as a potent modulator
of cytokine production and lethality in LPS-induced pathology
(17, 18, 19). Gene transfer with IL-4 improves survival in
lethal endotoxemia (20), and selective, compartmentalized
blockade of TNF- overproduction by IL-4 enhances pulmonary clearance
of Pseudomonas aeruginosa in mice (21). We have
recently shown that rIL-4 may protect animals from death in a toxic
shock model with the bacterium, correlating with decreased levels of
circulating TNF- soon after challenge (22). IL-13, a
cytokine that shares anti-inflammatory properties with IL-4 and
IL-10, protects mice from LPS-induced lethal endotoxemia (20, 23).
IL-9 is a T cell-derived cytokine that acts on various cell types, including T cells, mast cells, erythroid and myeloid progenitors, and B lymphocytes (reviewed in Refs. 24 and 25). In vitro, IL-9 production by Th clones is restricted to the Th2 subset. Evidence indicates that IL-9 is also expressed in vivo during the course of Th2 responses, through the activation of IL-4-dependent (26, 27) and IL-4-independent (28) mechanisms. While IL-9 has been shown to enhance resistance to helminths (29, 30, 31), its potential role in acute Gram-negative infection has not been explored yet. Because of the mutual regulation of IL-9 and IL-4 expressions, we have examined the effect of IL-9 administration in a shock model with P. aeruginosa, in which prophylactic IL-4 provides protection (22). We found that IL-9 was endowed with marked therapeutic activity in otherwise lethally infected mice. This was concomitant with early down-modulation of proinflammatory cytokines and induction of the anti-inflammatory cytokine IL-10.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hybrid (BALB/cCr x DBA/2Cr)F1 (CD2F1) mice were purchased from Charles River Breeding Laboratories (Calco, Milan, Italy). Mice of both sexes, ranging in age from 2 to 4 mo, were used.
Organism and infection
The origin and characteristics of the P. aeruginosa strain used in this study have been described elsewhere (32, 33, 34). The organism was routinely cultured in tryptic soy broth (Difco Laboratories, Detroit, MI) and incubated at 37°C for 18–24 h with constant aeration. For infection, overnight cultures were centrifuged, the soft pellet was resuspended in PBS, and 1010 cells (representing the LD902 in our model system) were injected i.v. Portions of suitable dilutions were also inoculated onto agar plates for precise enumeration of CFU. All deaths resulting from infection, as proven by clinical signs and histopathological examination, occurred within 3 days of microbial challenge and mostly within the first 24–48 h (mortality was routinely recorded for up to 7 days from challenge). Enumeration of CFU in the blood of infected mice was performed by standard procedures, by inoculating 0.1-ml blood samples onto nutrient agar plates (32).
Cytokines and Abs
Murine rIL-4 and rIL-9 (5 x 107
U/mg) were produced in the baculovirus system, as previously described
(35). Murine rIL-12 was a generous gift from Dr. B.
Hubbard (Genetics Institute, Cambridge, MA). Murine rTNF- and
rIFN- were from Genzyme (Cambridge, MA). Murine rIL-10 was from
PharMingen (San Diego, CA).
Rat anti-mouse IL-12 p40 mAb C17.8 was from Genzyme. Rabbit
anti-mouse IL-12 Ab was a generous gift from Dr. F. Fallarino
(University of Perugia, Perugia, Italy) (36). Anti-mouse
IFN- mAbs AN-18.17.24 and XMG1.2 and anti-mouse TNF- MP6-XT3
were purified from hybridoma culture supernatants by means of affinity
chromatography. Anti-mouse IL-10 mAbs JES5-2A5 and biotinylated SXC-1
were from PharMingen. For in vivo neutralization experiments, the SXC-1
mAb was purified from hybridoma culture supernatants using
chromatography on Thiophilic gel that retains IgM (Affiland, Ans-Liege,
Belgium).
In vivo treatments
LPS from P. aeruginosa (serotype 10) was obtained from Sigma (St. Louis, MO). For in vivo challenge, mice were injected i.p. with a predetermined LD90 (850 µg) of LPS, and survival was monitored over the next 7 days. rIL-4 was administered i.p. 24 h before bacterial challenge, at the dose of 3 µg/mouse given as a complex with 30 µg of anti-IL-4 mAb 11B11 (22). Various doses of rIL-9 were administered i.p. 1 and/or 24 h before bacterial challenge, unless otherwise stated. Heat inactivation of IL-9 to be used as a control treatment was achieved by autoclaving. Pentoxifylline (PTX; Sigma) was administered i.p. in PBS at 30 mg/kg 1 h before infection (34). For neutralization of IL-10, mice received 500 µg of SXC-1 mAb i.p. 2 h before bacterial challenge.
Cytokine assays
TNF bioactivity in sera was measured as cytotoxic activity to
WEHI 164 clone 13 murine fibrosarcoma cells, obtained through the
courtesy of P. van der Bruggen (Ludwig Institute for Cancer Research,
Brussels, Belgium). The assay was performed as described
(34), in the presence of LiCl, to optimize sensitivity to
TNF-mediated cytotoxicity and using a tetrazolium-based colorimetric
assay to estimate mortality of WEHI cells. The specificity of the assay
was determined by incubating samples with the neutralizing rat
anti-mouse TNF- mAb MP6-XT3. TNF titers were expressed as ng/ml,
calculated by reference to a standard curve constructed with known
amounts of rTNF-.
Plasma levels of IL-12 p40 were assayed by sandwich ELISA using C17.8
mAb and biotinylated polyclonal rabbit anti-mouse IL-12 Ab. The
sandwich ELISA for IFN- measurements involved the use of AN-18.17.24
mAb and biotinylated XMG1.2 mAb (37). IL-10 measurements
involved the use of mAb JES5-2A5 and biotinylated SXC-1 mAb
(38). The sensitivity limit was 
20 pg/ml for all
cytokines assayed by ELISA.
RNA preparation and PCR
These procedures, involving 30 cycles of amplification with an annealing temperature of 60°C, were previously described in detail (34, 38). ß-actin primers were purchased from Clontech Laboratories (Palo Alto, CA). The sequences of 5' sense and 3' antisense primers of IL-9 and IL-10 were as follows: 5' IL-9, GAT GAT TGT ACC ACA CCG TG; 3' IL-9, CCT TTG CAT CTC TGT CTT CTG G; 5' IL-10, TCC TTA ATG CAG GAC TTT AAG GGT TAC TTG; and 3' IL-10, GAC ACC TTG GTC TTG GAG CTT ATT AAA ATC.
The amplified DNA size was 540 bp for ß-actin, 234 bp for IL-9, and 256 bp for IL-10. The PCR products were analyzed by 1.5% agarose gel electrophoresis and visualized by ethidium bromide staining.
Statistical analysis
In the in vivo infection experiments, each experimental group consisted of at least eight animals and survival curves were analyzed by the Kaplan-Meier method. In the in vitro assays of cytokine determinations, Student’s t test was employed to analyze differences between groups.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have used a well-established model of toxic shock with P.
aeruginosa to determine whether IL-9, a Th2-associated cytokine,
is capable of exerting immunomodulatory effects similar to those
induced by IL-4 administration (22). In concurrence with
IL-4 or IL-9 treatment, mice were challenged i.p. with
1010 P. aeruginosa cells. IL-4 was
administered 24 h before challenge at the optimal dose of 3
µg/mouse, given as a complex with 30 µg of anti-IL-4 mAb 11B11,
which is known to improve bioavailability and increase the
effectiveness of IL-4 therapy (22). IL-9 was administered
twice at 4 µg/mouse, 24 and 1 h before challenge. Control mice
received either PBS or heat-inactivated IL-9. In several independent
experiments, IL-9 reproducibly and significantly
(p < 0.01) protected mice against the onset of
a lethal shock, with the adopted treatment schedule curing 80% of
the infected animals (representative experiment shown in Fig. 1
).
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compares this dosage with 1 or 5 µg of IL-9 administered once (-24
h) or twice (-24 and -1 h) before bacterial challenge. It is
interesting to note that the administration of 4 µg of IL-9 24 h
before challenge was associated with a 50% cure rate even in the
absence of a second (at -1 h) exposure to the cytokine. Although a
single IL-9 treatment near the time of infection (4 µg/mouse, up to
3 h postchallenge) would appear to marginally benefit the hosts,
no therapeutic activity was observed when IL-9 treatment was delayed
until 6 h after Pseudomonas challenge (data not
shown).
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Effect of IL-9 administration on production of proinflammatory cytokines
Using the same experimental model of lethal or sublethal P.
aeruginosa infection, we have previously demonstrated a strong
association between the development of a fatal septic shock and
production of TNF- (32, 33, 34). In addition, IL-12 and
IFN- are also proinflammatory cytokines with a putative pathogenetic
role in septic shock and endotoxemia (6, 7, 8). We therefore
measured serum levels of TNF-, IL-12 p40, and IFN- in mice
challenged with P. aeruginosa or LPS and treated with IL-9.
Mice received IL-9 at 24 and 1 h before challenge with P.
aeruginosa cells or an LD90 of LPS.
Circulating levels of TNF-, IL-12 p40, and IFN- were measured at
2, 4, 6, 8, and 24 h postchallenge (Fig. 3). With both live bacteria and LPS, IL-9
exerted a dramatic effect on the early expression of the cytokines
being assayed. At 2, 4, and 6 h from challenge, the respective
levels of TNF-, IL-12 p40, and IFN- were greatly reduced. The
most dramatic effect occurred with TNF-, whose expression was
reduced by 10-fold in P. aeruginosa-infected mice and
>2-fold in animals challenged with LPS. Interestingly, despite the
reduction induced by IL-9, the high baseline expression of circulating
TNF- in the latter mice still resulted in death of the majority of
the animals, an effect that could not be opposed by adding a third
administration of IL-9 at 1 or 4 h postchallenge (data not
shown).
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Phosphodiesterase inhibitors, which modulate the production of
TNF-, are known to improve outcome in experimental sepsis
(9). We have previously shown that PTX, a
phosphodiesterase inhibitor, is beneficial in mice given a lethal
inoculum of P. aeruginosa. The protection afforded by PTX
has been taken to indicate that TNF- overproduction is an important
mechanism of pathogenesis in our septic shock model (34).
We therefore wanted to examine whether the therapeutic effect of IL-9
administered postchallenge could be amplified by combined treatment
with suboptimal doses of PTX. Mice were administered the
phosphodiesterase inhibitor at 30 mg/kg 1 h before challenge with
P. aeruginosa. At 3 h of infection, the animals were
treated with 4 µg/mouse IL-9. Fig. 4
shows that neither PTX alone nor IL-9 alone resulted in significant
protection. However, combined treatment with IL-9 and PTX led to
survival of most of the infected animals.
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The apparently synergic effects of PTX and IL-9 administration in
Fig. 4
suggested that TNF- inhibition might not be the only
mechanism involved in the therapeutic activity of IL-9 in our model
system. As we have previously shown that the anti-inflammatory
cytokine IL-4 is produced during the course of infection with P.
aeruginosa (22), we measured serum levels of the
anti-inflammatory cytokines, IL-4 and IL-10, in mice challenged
with the bacterium or LPS and treated with IL-9 (Fig. 5). The animals were given IL-9 24 and
1 h before either type of challenge, and serum cytokine levels
were measured by ELISA at 2, 4, 6, 8, and 24 h. Although the
limited production of IL-4 peaking at 4 h of infection was
apparently unaffected by IL-9 treatment, a striking increase was
observed at 2 h in the IL-10 levels of
Pseudomonas-infected and IL-9-treated mice. Although to a
lesser extent, this effect was also evident after challenge with
LPS.
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). At 0.5, 1, 2, 4,
and 8 h of infection, we measured mRNA for IL-10 in IL-9-treated
and untreated mice. Although transcripts specific for IL-10 were hardly
detectable in the spleens of control mice, these transcripts were
greatly expressed soon after infection in the animals receiving
IL-9.
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To directly test the hypothesis that endogenous IL-10 could
mediate or contribute to the therapeutic activity of IL-9, we examined
the effect of IL-10 neutralization in Pseudomonas-infected
mice treated with 4 µg rIL-9 at 24 and 1 h before challenge. A
single injection of anti-IL-10 mAb administered 2 h before
infection resulted in 100% mortality in both IL-9-treated and
untreated mice (data not shown), thus apparently reversing the
beneficial effect of IL-9 therapy. However, in experiments not reported
in this work, we found that independent of any possible cotreatment,
IL-10 neutralization resulted per se in abnormal susceptibility to
challenge, as demonstrated by the development of a lethal shock in mice
administered otherwise sublethal inocula (e.g.,
109 P. aeruginosa cells). This
suggested that a basal production of IL-10 is an absolute requirement
for the host to cope with infection in our experimental model.
Therefore, the deleterious effect of IL-10 neutralization could not be
taken as definite evidence for an obligatory role of increased IL-10
secretion in the therapeutic activity of rIL-9. In line with these
observations was the finding that, both in IL-9-treated and untreated
mice, neutralization of IL-10 resulted in a 5-fold increase in the
levels of circulating TNF- soon after infection (15.3 ± 1.8
and 16 ± 2.1 ng/ml of TNF- for anti-IL-10-treated mice
with or without concurrent IL-9 therapy, respectively).
Expression of IL-9-specific transcripts in the spleens of Pseudomonas-infected mice
To investigate the possible role of endogenous IL-9 in
Gram-negative bacterial shock, we monitored mRNA levels of IL-9 in the
spleens of mice undergoing lethal vs sublethal challenge with P.
aeruginosa. Spleens were harvested at 0.5, 2, 4, 8, 24, or
120 h after inoculation of 1010 or
109 P. aeruginosa cells, and
PCR-assisted mRNA amplification was performed using specific primers
(Fig. 7). The timing and pattern of
message detection appeared to differ qualitatively in the spleens of
lethally vs sublethally infected mice. High levels of specific messages
were detected throughout the course of infection (up to day 5) in mice
eventually recovering from disease. In contrast, in mice developing
lethal shock, a progressive reduction in IL-9 mRNA expression was
observed starting 30 min postinfection. Barely detectable transcript
levels were found at 24 h, a time when the animals began to
die.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Septic shock is an often fatal condition, and excessive production of
proinflammatory cytokines is thought to contribute significantly to its
lethality. This concept is supported by much evidence derived from
studies in animal and in human systems in which the systemic injection
of LPS or live bacteria or the presence of bacterial infection is
associated with the sustained production of proinflammatory cytokines.
Various studies in animal models have demonstrated the protective
effect of anti-cytokine maneuvers, including the administration or
induced expression of the Th2 cytokines IL-10 (17, 18, 19) and
IL-4 (20). In addition, the anti-inflammatory cytokine
IL-13 has been found to provide protection from LPS-induced endotoxemia
in a manner that is similar to but distinct from that of IL-10
(23). We have recently shown that rIL-4 may exert a dual
effect on the resistance of mice to P. aeruginosa-induced
septic shock and production of TNF-. Improved survival and decreased
TNF- production are observed when the cytokine is administered
24 h before challenge, whereas, paradoxically, increased mortality
and overproduction of TNF- occur when the rIL-4 is given near the
time of infection (22).
Because of the interdependence and similarity of IL-9 activities with
those of Th2 cytokines, we have investigated any possible effect of
IL-9 administration on the development of a fatal shock according to
conditions under which prophylactic IL-4 confers protection. One or two
injections of rIL-9 increased survival to an extent similar to IL-4
(Fig. 1) and in a dose-dependent manner (Fig. 2) when a lethal inoculum
of P. aeruginosa was administered to mice. The effect
appeared to be IL-9 specific because survival was not affected in mice
receiving heat-inactivated IL-9 (Fig. 1). The recombinant cytokine
provided optimal protection when administered 1 day and 1 h before
challenge (Fig. 2); however, this protection decreased in a
time-dependent manner as the administration of IL-9 was delayed until a
maximum of 3 h after challenge (data not shown). Nevertheless,
under the latter conditions of administration, the therapeutic activity
of IL-9 could be greatly amplified by cotreatment with an inhibitor of
TNF- production (Fig. 4). As a matter of fact, the protective effect
of IL-9 correlated with remarkable decreases in the production of
circulating TNF-, IL-12, and IFN- (Fig. 3).
Several considerations can be made from these experiments. First, it is
likely that TNF-, IL-12, and IFN- are major proinflammatory
cytokines whose production in the host in response to live bacteria or
LPS is down-modulated by IL-9. Because anti-inflammatory cytokines
are known to be released as a regulatory mechanism in septic shock
(10), it is possible that endogenous IL-9 may contribute,
either directly or indirectly, to a compensatory response in septic
shock. Of interest, in the early hours after bacterial challenge, we
did not detect increased clearance of the bacterium from the blood of
mice cured by IL-9 therapy relative to controls succumbing to
challenge. This suggested that the beneficial effect of the exogenous
cytokine occurred primarily through interference with the cascade of
events ultimately leading to the onset of severe shock. Furthermore, we
obtained evidence for the early expression of IL-9-specific transcripts
in the spleens of mice challenged with Pseudomonas. This
expression lasted for at least 5 days postchallenge in mice recovering
from sublethal infection, but was reduced in the hours preceding death
in the lethally infected mice (Fig. 7). Finally, preliminary
experiments have shown that neutralization of endogenous IL-9 by
specific Ab may exacerbate the course of sublethal challenge with the
bacterium (data not shown).
Second, rIL-9 does not share the paradoxical effect of rIL-4 on
resistance of mice to P. aeruginosa-induced septic shock as
a function of time of administration relative to microbial challenge
(22). In fact, rIL-4 appears to exert inhibitory or
stimulatory effects on TNF- production depending on timing of
exposure, and such disparate effects correlate with the respective cure
or exacerbation of P. aeruginosa infection.
Third, the therapeutic activity of rIL-9 in our model may involve
multiple mechanisms. Because the peak in TNF- production after
challenge with live bacteria or LPS is an early event during the course
of lethal endotoxemia, it is likely that TNF- acts as an initiator
in the cascade of endogenous mediators that will direct the
inflammatory and metabolic responses eventually leading to severe shock
and organ failure (34). The ineffectiveness of
postchallenge therapy with IL-9 could be due to failure to interfere
with the initial TNF- release. However, the synergic effects of
early TNF- inhibition by PTX (which is per se ineffective under the
adopted treatment conditions; Fig. 4) and deferred IL-9 therapy suggest
that the recombinant cytokine may activate additional mechanisms that
are fully protective once the initial TNF- response has been
reduced. That the combined activity of PTX and IL-9 cannot be simply
explained by additive effects on TNF- production (each treatment
partially inhibiting TNF-) is suggested by the fact that IL-9
administration occurred at a time (i.e., 3 h postchallenge) when
circulating levels of TNF- had already begun to decline (Fig. 3 and
our unpublished data). On the other hand, it is interesting to note
that TNF- production was inhibited by PTX treatment alone, while
onset of endotoxic shock was not inhibited. This further substantiates
the concept that a reduction in circulating TNF- levels may be
necessary but not sufficient for blocking development of Gram-negative
bacterial shock.
In vitro studies have shown that IL-10 is a potent
macrophage-deactivating cytokine capable of suppressing the induction
of proinflammatory cytokines and up-regulating the production of IL-1R
antagonist (43, 44). By virtue of its ability to suppress
IL-12 release by macrophages, IL-10 also inhibits the production of
IFN- by T and NK cells (6, 7, 8). In vivo studies have
shown that selective IL-10 ablation by serotherapy or gene disruption
will result in high levels of circulating TNF- and IFN- and in
enhanced endotoxin sensitivity (17, 18, 19). We found that the
administration of an optimally protective regimen of IL-9 was
associated with the early (at 2 h) appearance of high levels of
circulating IL-10 in mice challenged with live bacteria. In contrast,
the limited IL-4 response induced by Pseudomonas challenge
at 4 h was not significantly affected by IL-9 administration (Fig. 5). IL-10-specific transcripts could be detected in the spleens of
IL-9-treated and infected mice (Fig. 6). Of interest, the IL-10
response induced by IL-9 in LPS-challenged mice was much lower than in
Pseudomonas-infected mice, and no IL-10 induction was
observed in the absence of bacterial or LPS challenge (Fig. 5 and data
not shown). As mentioned above, the LPS-treated mice would experience
sustained TNF- production and would eventually die.
An IL-10 dependence of IL-9 effects could not be firmly established by
the use of anti-IL-10 mAb in our model, as the ablation of
endogenous IL-10 would abnormally increase susceptibility to challenge
and levels of circulating TNF- in both IL-9-treated and untreated
mice. Yet, our present data suggest a complex, mutual regulation of
IL-9 and IL-10 productions within the context of the
innate/inflammatory response to infection. Both the cellular source and
the mechanism of IL-10 induction by IL-9 are unclear, yet it is
possible that one major target of IL-9 activity is represented by the
monocyte/macrophage, which could be both deactivated and primed to
release IL-10 upon IL-9 treatment. IL-9 could also be acting on
different cell types, including B and T lymphocytes, resulting in the
early induction of IL-10 that would in turn act on macrophages. This
would explain the generalized suppression of the proinflammatory
cytokines, TNF-, IL-12, and IFN-, all of which are known to be
down-regulated by IL-10 (6, 17, 19).
In conclusion, our data suggest that IL-9 provides protection from Pseudomonas-induced lethal shock via multiple mechanisms that may include suppression of proinflammatory cytokines and induction of IL-10. Although a possible IL-10 dependence of IL-9 production has previously been described in different experimental models, our data provide the first evidence for the occurrence of bidirectional influences between IL-9 and IL-10 productions in innate immunity. Due to its potent and multiple activities involving modulation of proinflammatory and anti-inflammatory cytokines, IL-9 can be added to the list of cytokine immunomodulators that might be beneficial in the treatment of septic shock.
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Footnotes |
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2 Abbreviations used in this paper: LD90, lethal dose 90, inoculum size or dose at which 90% mortality occurs; PTX, pentoxifylline.
Received for publication September 28, 1999. Accepted for publication February 2, 2000.
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I. J. Elenkov, R. L. Wilder, G. P. Chrousos, and E. S. Vizi The Sympathetic Nerve---An Integrative Interface between Two Supersystems: The Brain and the Immune System Pharmacol. Rev., December 1, 2000; 52(4): 595 - 638. [Abstract] [Full Text] [PDF]
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