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Infection and Immunity, June 2000, p. 3322-3326, Vol. 68, No. 6
Mycobacterial Research Laboratories,
Department of Microbiology,1 and
Department of Pathology,2 Colorado
State University, Fort Collins, Colorado, 80523
Received 30 December 1999/Returned for modification 25 February
2000/Accepted 22 March 2000
Immunity to Mycobacterium tuberculosis is dependent
upon the generation of a protective gamma interferon
(IFN- Interleukin-6 (IL-6) is a
pleiotropic cytokine capable of inducing multiple effects upon many
target cells. It is involved in the differentiation and proliferation
of T and B cells (1, 10, 13) and acts in conjunction with
the other proinflammatory cytokines tumor necrosis factor alpha
(TNF- The importance of IL-6 in protection from mycobacterial infections is
no less complex an issue than for other models. Specifically, Ladel and
colleagues reported that while IL-6 was not required to inhibit the
growth of Mycobacterium bovis BCG in vivo, IL-6 KO mice were
more susceptible than control mice to very high doses of intravenously
delivered M. tuberculosis (16). In addition, other studies have reported that IL-6 depletion results in exacerbation of M. avium infection (1) and also reduces the
protective effect of culture filtrate protein vaccination against
aerogenic M. tuberculosis infection (17). A key
observation in the above-mentioned studies was that the absence of IL-6
resulted in reduced production of the protective cytokine gamma
interferon (IFN- Given the above-mentioned data, it would be reasonable to hypothesize
that IL-6 plays a protective role in mycobacterial infection. However,
the previous studies did not directly address the role of IL-6 in
primary infection of the natural target organ, the lung. What they did
address is the importance of IL-6 in the differentiation of
antigen-exposed Th cells into an IFN- In the intravenous challenge model cited above, the increased
susceptibility of IL-6 KO mice correlated with increased expression of
IL-4 (16). The decrease in IFN- To address the issues raised above, both control and KO mice were
infected aerogenically with a low-dose aerosol of M. tuberculosis. Both bacterial growth and development of immune
parameters were followed over time. We report here that the absence of
IL-6 led to a delay in the induction of protective immunity with a
subsequent early increase in bacterial load; however, the absence did
not affect the induction of normal protective memory responses. The absence of IL-4 did allow more rapid expression of the protective IFN- Mice.
Female IL-6 KO or IL-4 KO mice and C57BL/6 wild-type
controls were purchased from The Jackson Laboratory, Bar Harbor, Maine. KOs were generated by targeted gene disruption of embryonic stem cells,
which were introduced into C57BL/6/129 blastocysts (14, 15).
Heterozygous mice (+/ Bacteria and infection.
M. tuberculosis strains Erdman
and CSU 93 were grown from laboratory stocks in Proskauer-Beck liquid
medium to mid-log phase, aliquoted, and then frozen at
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Interleukin-6 Induces Early Gamma Interferon
Production in the Infected Lung but Is Not Required for Generation of
Specific Immunity to Mycobacterium tuberculosis
Infection
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
)-producing T-cell response. Recent studies have suggested that
interleukin-6 (IL-6) is required for the induction of a protective
T-cell response and that IL-4 may suppress the induction of IFN-. To
evaluate the role of the cytokines IL-6 and IL-4 in the generation of
pulmonary immunity to M. tuberculosis, IL-6 and IL-4
knockout mice were infected with M. tuberculosis via
aerosol. The absence of IL-6 led to an early increase in bacterial load
with a concurrent delay in the induction of IFN-. However, mice were
able to contain and control bacterial growth and developed a protective
memory response to secondary infection. This demonstrates that while IL-6 is involved in stimulating early IFN- production, it is not
essential for the development of protective immunity against M. tuberculosis. In contrast, while the absence of IL-4 resulted in
increased IFN- production, this had no significant effect upon
bacterial growth.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
) and IL-1 to initiate the early inflammatory response
following infection (10). The specific role of IL-6 in
response to a pathological agent varies markedly, depending upon the
agent, as is illustrated by the varied consequences of experimental
infection in the IL-6 gene-disrupted (knockout [KO]) mouse. Infection
by rapidly growing pathogens such as Listeria and
Salmonella spp. results in increased susceptibility (9,
14, 28), while little difference has been noted between IL-6 KO
and wild-type mice infected with the slow-growing bacterium Leishmania major (21).
) and, in one study, increased production of IL-4
(16).
-producing phenotype (17) and the importance of IL-6 in responding to an acute
bacterial infection of the visceral organs (16). The
low-dose aerosol model of M. tuberculosis mimics the natural
route of infection and provides a low challenge dose, enabling the mice
to develop strong protective immunity and contain the infection over a
prolonged period (26). Use of the aerosol model therefore
allows the function of IL-6 in the development of early, possibly
unique, protective immune responses in the lung to be determined.
seen in IL-6 KO mice may have been a direct result of the lack of IL-6 (as suggested by the work
of Leal and colleagues reported in reference 17). It is also possible, however, that the excess IL-4 was responsible for the
downregulated IFN- production and therefore the increased susceptibility. IL-4 is well known to be able to downregulate protective IFN- responses (3, 20), and it is entirely
plausible that IL-4 could contribute to the loss of the protective
IFN- response seen in the murine model of tuberculosis
(23). We were therefore also interested in the ability of
the IL-4 KO mouse to generate protective T-cell responses in response
to aerogenic infection.
response, but this failed to alter the growth of bacteria within the lung.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
) were then bred to produce both homozygous KOs
and wild-type controls.
70°C. Mice
were infected using a Middlebrook Airborne Infection apparatus
(Middlebrook, Terre Haute, Ind.) such that within each experiment, all
groups were exposed simultaneously to the same dose, which results in
approximately 100 CFU of M. tuberculosis being deposited in
the lungs of each mouse (4, 5, 8, 24, 26, 27). The numbers
of viable bacteria in the lung, spleen, and liver were determined at
various time points by plating serial dilutions of organ homogenates on nutrient Middlebrook 7H11 agar and counting bacterial colonies after 21 days of incubation at 37°C. The data are expressed as the
log10 of the mean number of bacteria recovered per organ
(four animals).
Preparation of lung and spleen cells. Lungs were aseptically excised and washed free of blood by injection of 10 ml of Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS), penicillin at 100 U/ml, streptomycin at 100 µg/ml, 10 mM HEPES, 2 mM glutamine, and nonessential amino acids (DMEM-10% FCS) through the heart. The tissue was then finely sliced with sterile razor blades, and tissue from each individual lung was incubated for 60 min in 10 ml of medium containing 0.25% Dispase (Boehringer Mannheim). Undigested tissue was forced through a mesh sieve and centrifuged to pellet cells. The preparations underwent NH4Cl treatment to remove any remaining red blood cells. Cells were then washed, counted, and resuspended in DMEM-10% FCS. Spleen cell suspensions were prepared by forcing the spleen through a mesh sieve, followed by washing, lysis of red blood cells, and resuspension in DMEM-10% FCS.
Culture and assay for cytokine release. Cultures of 2 × 106 spleen cells, pooled from four mice per group, with or without stimulation by 2 × 106 CFU of M. tuberculosis were incubated in triplicate in a 1-ml volume of DMEM-10% FCS in 24-well plates for 72 h. Cultures of 2 × 105 lung cells, from four individual mice, were incubated in a 200-µl volume of DMEM-10% FCS in 96-well plates for 5 days with antigenic stimuli identical to those used with spleen cells.
Cytokines released into the culture supernatant were detected using a sandwich enzyme-linked immunosorbent assay (ELISA) with appropriate antibody pairs as follows: IFN-, R4-6A2 and XMG1.2; IL-6, MP5-20F3
and MP5-32C11; IL-4, BVD4-1D11 and BVD6-24G2 (Pharmingen, San Diego,
Calif.). Immunoplate Maxisorb 96-well plates (Nunc, Naperville, Ill.)
were used. ELISAs were performed by following the manufacturer's directions.
Isolation of mRNA and analysis of levels of mRNA in infected lung
tissue.
Relative amounts of mRNAs for IFN-, IL-12 p40 chain,
TNF-, and IL-2 were determined by a quantitative reverse
transcriptase PCR protocol as previously described (4).
Briefly, tissues were excised, placed in Ultraspec (Cinna/Biotecx,
Friendswood, Tex.), and homogenized and RNA was extracted by a
phenol-chloroform extraction process. One microgram of total RNA was
reverse transcribed, diluted, and subjected to PCR expansion of
cytokine-specific cDNA. Fluorescein-tagged cytokine sequence-specific
probes were used to determine the amount of cytokine-related product.
The fluorescein was detected using an enhanced-chemiluminescence kit
(ECL; Amersham, Arlington Heights, Ill.). A limiting number of cycles
was used, generating a log-linear relationship between the
chemiluminescence signal and the amount of readable cytokine mRNA. The
signal derived from four infected mice is divided by the signal derived
from four appropriate noninfected control mice, and data are expressed as the mean fold increase in the infected signal over the uninfected signal.
Statistical analysis. Differences between the means of experimental groups were analyzed using the Student t test. Differences were considered significant at P < 0.05.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
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Increased bacterial growth in IL-6 KO but not IL-4 KO mice
following low-dose M. tuberculosis aerosol infection.
In a first series of experiments, the ability of IL-6 KO mice to
control infection with M. tuberculosis was assessed. Control and KO mice were simultaneously infected with 102 CFU of
M. tuberculosis Erdman via the aerogenic route, and the number of bacteria was assessed at intervals after infection. Within 14 days postinfection, IL-6 KO mice had approximately 1 log more bacteria
in their lungs than did the control mice (Fig. 1A). These mice maintained a higher
bacterial load for the duration of the study, although bacterial growth
was controlled and dissemination of bacteria into the spleen and liver
did not differ significantly between the two mouse strains (Fig. 1A).
|
Absence of IL-6 decreases early IFN- production following
M. tuberculosis infection.
Production of IFN- is a
critical requirement for protective immunity against M. tuberculosis (6, 11). To assess the role of IL-6 in
inducing IFN- production, lung cells from M. tuberculosis-infected mice were cultured in vitro with live
M. tuberculosis bacteria. IL-6 KO mice produced no
detectable IFN- at 7 days postinfection and only half of the IFN-
of wild-type mice at 14 days (Fig. 2A).
To confirm that IL-6 was available at this early stage of infection,
this cytokine was detected in cultures from control infected, but not
uninfected, mice as early as day 7 (data not shown).
|
than did control mice while
IL-4 KO mice had significantly increased production of IFN- at this
same time point (Fig. 2B). No IL-4 was detectable (limit, 75 pg/ml) in
the control infected cultures (data not shown).
IFN- mRNA expression is difficult to detect during the early (days 0 to 15) phase of low-dose aerogenic infection (5, 27). By day
30, however, mRNA is detectable in the lungs of control mice and at
this time point the IL-6 KO mice exhibit a decreased ability to express
mRNA for IFN- (Fig. 3). Interestingly, IL-4 KO mice are able to express IFN- mRNA as early as day 14, which
is earlier than the control mice. Thus, while it is necessary to
restimulate lung cells ex vivo to observe the early defect in IFN-
production in IL-6 KO mice, the available reverse transcriptase PCR
data do support the hypothesis that IL-6 KO mice are less able to
express IFN- in response to aerogenic infection in vivo.
|
Absence of IL-6 does not affect the generation of a protective
memory response against M. tuberculosis.
As discussed above,
IL-6 appears to play a role in the generation of specific protective
immunity, through the differentiation of T lymphocytes to an
IFN--producing phenotype (1, 19). Our initial experiments
demonstrated the decreased ability of IL-6 KO mice to produce IFN-
from mixed cell populations derived from both the lung and the spleen.
While the IFN- may have been derived from antigen-specific T cells,
there are many other potential sources of this cytokine in the
mixed-population studies reported here. In order to address the role of
IL-6 in the induction of protective memory T lymphocytes, the level of
protection mediated by prior exposure to M. tuberculosis was
compared for both IL-6 KO and control mice. In accordance with previous
studies, neither the control nor the IL-6 KO memory mice exhibited
increased protection compared to naive mice at day 10 of infection
(5). Importantly, however, both the control and IL-6 KO mice
exhibited a similar significant decrease in bacterial growth compared
to the naive mice by day 25 (Fig. 4).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
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This study demonstrates that IL-6 is required for the rapid
expression of an initial protective IFN- response during M. tuberculosis infection. This early response occurs in the lung and
is important in the initial containment of mycobacterial growth in this
organ. The early lack of containment seen in the absence of IL-6 is
compensated for when the acquired immune response is expressed. In
addition, IL-6 is not required for the generation of effective memory
immunity, as evidenced by the ability of IL-6 KO mice to express strong protective immunity upon rechallenge.
Our study extends an earlier study by Ladel and colleagues (16), who found a protective role for IL-6 in high-dose intravenous infection with M. tuberculosis. In this model, exacerbation of growth was seen in the spleen, liver, and lung, with IL-6 KO mice succumbing to infection beginning 50 days after infection. The fact that IL-6 KO mice did not die in the experiments described here is not contrary to the observations of Ladel (16). In both studies, increased growth of bacteria was seen early in infection; however, when the initial dose was low (and when the high-dose bacteria were less virulent, i.e., BCG [16]), IL-6 KO mice were eventually able to contain the infection.
The precise mechanism by which IL-6 mediates its protective effects in models of infectious disease has not been determined. It is well documented, however, that IL-6 can affect the initiation and development of both the innate and acquired responses in vivo (30). The data presented here strongly suggest that IL-6 has an early, probably innate, protective role which cannot be compensated for by other cytokines. Specifically, the observed kinetics of the increased susceptibility seen in both naive and memory IL-6 KO mice support this hypothesis, as susceptibility precedes the normal expression of protective immunity in this organ (5) and is not improved by the induction of a memory state in the IL-6 KO mouse.
Previous studies with Listeria monocytogenes and
Candida albicans have implicated neutrophils as major
components of the IL-6 protective response to these agents. In both of
these models, the protective effect of IL-6 was abrogated in the
absence of neutrophils and one consequence of the absence of IL-6 was
defective neutrophilia in response to infection (9, 28).
IL-6 has been shown to activate human neutrophils (2), and
we have recently identified a protective nonphagocytic role for these
cells in tuberculosis infection wherein the depletion of neutrophils
resulted in reduced IFN- mRNA in the infected organ (25).
A hypothesis generated by these observations is that there may be a
novel protective mechanism in the M. tuberculosis-infected
mouse lung which is dependent upon IL-6 recruitment/activation of
neutrophils which then facilitates a rapid IFN- response.
Interestingly, both IL-6 KO mice and p47phox KO mice (which lack the ability to generate reactive oxygen intermediates [ROI]) exhibit almost identical phenotypes when aerogenically challenged with M. tuberculosis (8). This similarity may be due to the importance of ROI in the initiation of IL-6 mRNA expression, particularly in the lung (8, 12, 29, 31). The increased susceptibility to early bacterial growth observed in both models may therefore occur as the result of disruption ROI induction of IL-6 (data reported here and in reference 8).
Notwithstanding the strong evidence for an innate role for IL-6 in the
control of M. tuberculosis infection, several reports have
implicated IL-6 in the initiation and maintenance of acquired antigen-specific cellular immunity. The data reported here show that
the susceptibility of IL-6 KO mice occurred prior to the expression of
normal cellular immunity (5) and did not affect the
expression of protective memory immunity. In addition, both IFN-
expression and control of bacterial growth in the lung were not
compromised once the early stage of infection was over. These observations suggest that in the presence of a viable bacterial infection, IL-6 is not essential for the induction of memory immunity and that protective IFN--producing cells can be induced in the absence of early IL-6-dependent IFN-. This is in contrast to the
data reported for both M. avium and L. monocytogenes infections (1, 19), wherein IL-6 plays a
positive role in the generation of a protective memory response. Thus,
while the presence of IL-6 is important for the induction of
antigen-specific memory T-cell development during vaccination
(17), the presence of a live M. tuberculosis
infection abrogates the requirement for this cytokine. It is probable
that other cytokines, such as IL-12 (7) and TNF-
(27), that are induced by live M. tuberculosis
compensate for the lack of IL-6 in the induction of antigen-specific
IFN--producing T cells.
In other models of infection, IL-6 KO mice express increased levels of
IFN--downregulating cytokines such as IL-4 (16) and IL-10
(28). It is possible, therefore, that the protective activity of IL-6, as presented here, was mediated by inhibition of
IL-4. We were able to examine this question by infecting mice that lack
IL-4. Interestingly, the lack of IL-4 did result in earlier and
increased expression of IFN-, thus supporting the hypothesis that
IL-4 did, indeed, inhibit IFN- production. It was noticeable,
however, that no increased antimycobacterial effect was seen in IL-4 KO
mice, suggesting that sufficient IFN- was produced in the presence
of IL-4 and thus any role of IL-6 in limiting the effects of IL-4 in
control mice was essentially moot.
In conclusion, an inability to produce IL-6 in response to infection is
not lethal when the dose or virulence of the infective agent is
limited. In contrast, a high dose or a rapidly growing pathogen can
overwhelm the kind of moderately compromised response seen in IL-6 KO
mouse. What we demonstrate here is that IL-6 is required to initiate a
very early, possibly innate, IFN- response, which then limits
bacterial growth until acquired cellular immune responses are
expressed. In the normal animal, this early IFN- response appears to
be optimal, as increasing this response (by removing IL-4, for example)
fails to augment bacterial control. The precise nature of this early
mechanism mediating control of M. tuberculosis in the lung
has not been elucidated; this paper begins to identify some of the
components of this mechanism.
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ACKNOWLEDGMENTS |
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We thank the staff of the Laboratory Animal Center, Colorado State University, for animal care and W. Mueller for permission to use the IL-4 KO mice.
This work was supported by National Institutes Health grant AI-40488.
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FOOTNOTES |
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* Corresponding author. Present address: Mycobacteria Research Laboratory, Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No 6, Camperdown, NSW 2042, Australia. Phone: 61-2-9565-6114. Fax: 61-2-9565-6101. E-mail address: B.Saunders{at}centenary.usyd.edu.au.
Editor: J. D. Clements
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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