Roles of Interleukin-17 in an Experimental Legionella pneumophila
Yoshifumi Kimizuka,a,bSoichiro Kimura,aTomoo Saga,aMakoto Ishii,bNaoki Hasegawa,cTomoko Betsuyaku,bYoichiro Iwakura,d
Kazuhiro Tateda,aand Keizo Yamaguchia
Department of Microbiology and Infectious Disease, Toho University School of Medicine, Tokyo, Japana; Division of Pulmonary Medicine, Keio University School of
Medicine, Tokyo, Japanb; Center for Infectious Diseases and Infection Control, Keio University School of Medicine, Tokyo, Japanc; and Center of Experimental Medicine
and System Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japand
control of a variety of infectious diseases. Although Legionella pneumophila, an intracellular bacterium found widely in the en-
duringLegionella pneumoniaisunknown.Inthepresentstudy,weusedanexperimental Legionellapneumoniainfectiontoclar-
kines IL-6 and TNF-? was observed in IL-17A/F-deficient mice (BALB/c background) infected with L. pneumophila. Moreover,
IL-17A/F-deficient mice also eliminated L. pneumophila more slowly and were less likely to survive a lethal challenge. These re-
sults demonstrate that IL-17A/F plays a critical role in L. pneumophila pneumonia, probably through induction of proinflam-
nate and adaptive immune systems (9). It contributes to host re-
sponses to a variety of immunological and inflammatory
disorders, such as collagen disease (4), allograft rejection (45),
tumor (2), allergy (21), and infectious diseases resulting from in-
cus pneumoniae, and Candida albicans (29). IL-17 is secreted by a
variety of cells, including T helper type 17 (Th17) cells, natural
killer cells, and ?? T cells, thereby inducing Th17-type host re-
sponses characterized by production of proinflammatory cyto-
lates several chemokines, such as macrophage inflammatory
protein 1 (MIP-1), MIP-2, and monocyte chemoattractant pro-
tein 1 (MCP-1), which, in turn, attract inflammatory cells to the
tion of granulocyte colony-stimulating factor (G-CSF) and stem
cell factor (SCF) and potentiates neutrophilic cytotoxicity and
phagocytosis (35). It is reported to enhance the function and sur-
vival of recruited macrophages in the airway (36).
Because IL-17 is a strong inducer of neutrophil-chemotactic
factors, it has been suggested to play an important role in the
pathogenesis, severity, and outcome in pneumonia caused by in-
fection with Legionella pneumophila. L. pneumophila is a ubiqui-
tous, Gram-negative facultative intracellular bacillus that fre-
quently causes a life-threatening pneumonia, especially in
immunocompromised individuals (23, 32). Legionella infections
usually result from inhalation of contaminated aerosols from en-
vironmental sources. Once the bacteria are in the lungs, they pre-
dominantly infect and multiply within monocytes and macro-
phages (13, 24, 28). Mortality rates of up to 50% have been
nterleukin-17 (IL-17) has recently received considerable atten-
tion because of its important role in cross talk between the in-
challenging infectious disease (8, 30, 41).
Cellular immunity and Th1-type cytokine responses are be-
cytokines such as gamma interferon (IFN-?), tumor necrosis fac-
Legionella infection (7, 10, 39). However, the roles of IL-17 in
pathogenesis of, and host defenses against, Legionella pneumonia
still require elucidation.
pathogenesis and lethal sensitivity of L. pneumophila pneumonia
two main factors in the IL-17 protein family that are known to
play an important role in antimicrobial host defenses and immu-
teria, viruses, and parasites (6, 15, 16, 26, 29). IL-17A and IL-17F
appear to bind the same receptor complexes, comprising IL-17
receptor A and IL-17 receptor C (42, 54), and therefore appear to
have similar biological functions (16). We measured quantities of
Received 1 July 2011 Returned for modification 25 July 2011
Accepted 23 November 2011
Published ahead of print 5 December 2011
Editor: B. A. McCormick
Address correspondence to Soichiro Kimura, firstname.lastname@example.org.
Supplemental material for this article may be found at http://iai.asm.org/.
Copyright © 2012, American Society for Microbiology. All Rights Reserved.
0019-9567/12/$12.00 Infection and Immunityp. 1121–1127 iai.asm.org
Legionella pneumonia and examined stimulation of proinflam-
matory cytokines in response to various levels of IL-17A and IL-
17F. We also compared proinflammatory cytokine induction lev-
els, leukocyte numbers, gene expression of CXC chemokines, and
total numbers of bacteria in the lungs of wild-type and IL-17A/F-
deficient mice (BALB/c background). Finally, we investigated
nella pneumonia. Cumulatively, our data strongly indicate that
MATERIALS AND METHODS
Animals. Specific-pathogen-free 5- to 8-week-old male BALB/c (Charles
River Laboratories, Kanagawa, Japan), C57BL/6J (Charles River Labora-
tories), and A/J (Sankyo Laboratory, Tokyo, Japan) mice were quaran-
tined for 1 week after reception. IL-17A/IL-17F double knockout mice
(Il17a?/?Il17f?/?) on a BALB/c genetic background were previously es-
All the studies were performed in mice of the BALB/c background. All
imal care facility at Toho University School of Medicine (Tokyo, Japan)
until the day of sacrifice. Experiments were conducted according to our
institution’s ethical guidelines for animal experiments and safety guide-
lines for gene manipulation experiments. Animal protocols were ap-
proved by the institutional animal care and use committee (approval
L. pneumophila inoculation. Clinical isolates of L. pneumophila Su-
zuki, a serogroup 1 strain stocked at Toho University Hospital (38), were
prepared as previously reported (37). Animals were anesthetized intra-
muscularly with ketamine at 7 mg/kg of body weight and xylazine at 15
Preparation of BM-M? and their stimulation with L. pneumophila
and recombinant IL-17. Bone marrow-derived macrophages (BM-M?)
previously described (3). The cells were cultured in 96-well tissue culture
plates (105cells per well) and used for BM-M? experiments. After the
the indicated multiplicity of infection (MOI) for 2 h. At the end of the
were removed by two washes with fresh medium. The cells were subse-
quently incubated at 37°C in a humidified atmosphere containing 5%
CO2. At the indicated time points, culture supernatants were collected,
and the infected macrophages were lysed as previously described (51).
So that we could investigate the effects of elevated IL-17A and IL-17F
levels during Legionella pneumonia on other inflammatory cytokines, we
incubated murine BM-M? for 24 h with increasing doses of IL-17A or
infection (MOI of 1.0). Culture supernatants of five different samples
stored at ?40°C until used for enzyme-linked immunosorbent assays
(ELISAs) (see below). Recombinant, endotoxin-free mouse IL-17A and
IL-17F were obtained from R&D Systems (Minneapolis, MN).
were sacrificed by CO2asphyxia. Their tracheas were exposed and intu-
bated using a polyethylene catheter with a 1.7-mm outer diameter. Bron-
saline (PBS) containing a complete protease inhibitor cocktail tablet
(Roche, Indianapolis, IN). BAL fluid (BALF) samples were pooled for
each animal. Leukocyte numbers were counted with a hemocytometer.
centrifuge; Shandon Scientific, Ltd., Astmoor, United Kingdom) stained
with May-Giemsa stain. The remaining BALF was stored at ?20°C until
Lung harvests for analysis. After the mice had been sacrificed, their
chests were opened, and the pulmonary vasculature was perfused with 1
ml of saline via the right ventricle. Whole lungs were removed, and left
lungs were homogenized under a vented hood with a homogenizer (IKA
inhibitor cocktail tablet and 0.2 mM phenylmethanesulfonyl fluoride.
yeast extract agar supplemented with ?-ketoglutaric acid (BCYE?) after
serial 1:10 dilution in saline. The remaining homogenates (900 ?l) were
Supernatants were collected and stored at ?20°C until use. Right lungs
use in evaluation of mRNA expression (see below).
Cytokine/chemokine measurements. Cytokines and chemokines
were measured with IL-17A, IL-17F, IL-6, TNF-?, MCP-1, and MIP-2
mouse ELISA kits (R&D Systems), according to the manufacturer’s pro-
Gene expression analysis. Total RNA was isolated from lungs using
RiboPure kits (Ambion), according to the manufacturer’s instructions.
which it was reverse transcribed using a High-Capacity cDNA Reverse
Transcription Kit (Applied Biosystems, Foster City, CA). Data analysis
utilizing the SYBR green real-time reverse transcription-PCR (RT-PCR)
(Applied Biosystems). We used the following PCR primers: keratinocyte-
derived chemokine (KC), 5=-GCTGGGATTCACCTCAAGAA-3= (for-
ward) and 5=-TCTCCGTTACTTGGGGACAC-3= (reverse); MIP-2, 5=-C
GCCCAGACAGAAGTCATAG-3= (forward) and 5=-TCCTCCTTTCCA
GGTCAGTTA-3= (reverse); LIX, 5=-GGTCCACAGTGCCCTACG-3=
(forward) and 5=-GCGAGTGCATTCCGCTTA-3= (reverse); IL-12p35,
5=-CACCCTTGCCCTCCTAAACC-3= (forward) and 5=-CACCTGGCA
GGTCCAGAGA-3= (reverse); IFN-?, 5=-GGATATCTGGAGGAACTGG
CAA-3= (forward) and 5=-TGATGGCCTGATTGTCTTTCAA-3= (re-
verse); IL-4, 5=-CTCATGGAGCTGCAGAGACTCTT-3= (forward) and
5=-CATTCATGGTGCAGCTTATCGA-3= (reverse); ?-actin, 5=-AGAGG
GAAATCGTGCGTGAC (forward) and 5=-CAATAGTGATGACCTGG
calculated using the 2???CT(where CTis threshold cycle) method (22)
using the housekeeping gene ?-actin as a reference standard for the
amount loaded and the quality of the cDNA.
Statistical analysis. All values are expressed as means ? standard er-
ror (SE). Data were analyzed with one-way analyses of variance
using the Kaplan-Meier method and were analyzed by log rank tests. Sig-
nificance was defined as a P value of ?0.05.
1 day after inoculation of L. pneumophila and then rapidly de-
clined to baseline values over the next 6 days (Fig. 1).
tory cytokines in macrophages. As shown in Fig. 2, the addition
of IL-17A or IL-17F greatly increased Legionella-induced produc-
tion of IL-6, TNF-?, and IL-1?, from 3- to over 10-fold by cul-
tured macrophages from BALB/c mice. These cytokines were
maximally induced by different optimal concentrations of IL-
17A and IL-17F though increases were significantly different
from baseline levels at all doses (1 pg to 10 ng). Similar results
in IL-6 and TNF-? production were observed in C57BL/6J and
A/J mice (see Fig. S1 in the supplemental material). On the
other hand, the proinflammatory mediator response in the un-
Kimizuka et al.
iai.asm.orgInfection and Immunity
infected cells was only slightly augmented by stimulation with
either IL-17A or IL-17F.
Proinflammatory cytokine production in the lungs of IL-
17A/F-deficient mice infected with Legionella. In the lungs of
increase in IL-6, TNF-?, and IL-1? levels on day 2 (Fig. 3A to C).
had significantly lower peaks (TNF-?) (Fig. 3B) or no peak at all
our BM-M? experiments, no significant differences in MCP-1
production were observed between wild-type and IL-17A/F-
deficient mice (Fig. 3D).
and cytokines. In the week following infection with Legionella,
similar BALF total cell numbers (Fig. 4A). However, there were
significant differences in proportions of specific inflammatory
cells. Specifically, on day 2, neutrophils, macrophages, and lym-
phocytes constituted 71.8, 25.9, and 2.3% of the cells in wild-type
BALF and 47.5, 48.3, and 4.2% of cells in BALF of IL-17A/F-
deficient mice, respectively.
Correspondingly, gene expression of the pulmonary CXC
mice than in wild-type mice (Fig. 4B). In addition, significantly
lower MIP-2 levels were observed in the lungs of IL-17A/F-
deficient mice (Fig. 4C). Wild-type and IL-17A/F-deficient mice
did not have significantly different levels of IL-12, IFN-?, or IL-4
gene expression (Fig. 4B).
FIG 1 Production of IL-17A and IL-17F in the lung during L. pneumophila pneumonia in a mouse model. IL-17A (A) and IL-17F (B) levels are shown as a
function of time after the inoculation of approximately 105CFU of L. pneumophila. All bars indicate mean ? SE (n ? 6/group). *, P ? 0.05 in comparison with
a negative control. Similar results were obtained across three repeat experiments.
FIG 2 Stimulation of macrophage (BALB/c) proinflammatory cytokines, as indicated on the figure, by IL-17A and IL-17F at 24 h after infection with L.
pneumophila (106CFU/ml; MOI of 1.0). All bars indicate mean ? SE (n ? 5/group). *, P ? 0.01 in a comparison with the infection-only group; **, P ? 0.05 in
a comparison between IL-17A and IL-17F. The results are representative of three independent experiments.
IL-17 in Legionella Pneumonia
March 2012 Volume 80 Number 3 iai.asm.org 1123
L. pneumophila. Pulmonary bacterial burdens were similar in
wild-type and IL-17A/F-deficient mice (BALB/c background) on
5). However, on day 7, IL-17A/F-deficient mice had approxi-
Survival of mice challenged with lethal doses of L. pneumo-
phila. When challenged with Legionella (?107CFU), wild-type
mice had significantly higher survival rates than IL-17A/F-
deficient mice (BALB/c background) (69% versus 38% at day 21;
P ? 0.05) (Fig. 6). These results indicate that IL-17A/F activity is
critical in preventing lethality of infection with Legionella pneu-
An increasing number of studies have documented the impor-
tance of IL-17 in immune responses to a variety of infectious dis-
IL-17A/F against L. pneumophila, an intracellular pneumonia
pathogen. Further, our findings suggest that the beneficial effects
of IL-17A/F may be associated with robust induction of inflam-
ance of L. pneumophila from the lungs and decreases in
The addition of IL-17A and IL-17F greatly increased Legionella-
imum cytokine inductions were produced by different concentra-
to suppression. Although the mechanisms behind, and implications
suggest that IL-17-dependent cytokine/chemokine production has
fine-tuning mechanisms, including optimal concentrations, IL-17
receptor specificity, intracellular signaling, and a positive/negative
responses and IL-17 production (44). In contrast, however, our re-
and IL-4 levels in control and IL-17-deficient mice. Thus, we con-
Few previous studies have employed IL-17-deficient or IL-17
receptor-deficient mice in order to investigate the cytokine’s role
in immune responses to pathogenesis. Among IL-17 receptor-
neutrophil recruitment and bacterial clearance were impaired,
and lethal sensitivity was higher (50). Likewise, IL-17 receptor-
deficient mice with systemic Candida albicans infections had
Listeria monocytogenes infection model demonstrated that IL-17
produced by ?? T cells plays a critical role in neutrophil recruit-
ment and eradication of bacteria (11, 25). IL-17 has also been
(52) as IL-17 blockades or deficiencies during infection led to
FIG3 Proinflammatory cytokine production in the lungs of wild-type and IL-17A/F-deficient mice (BALB/c background) during the week following infection
with L. pneumophila. The production of IL-6, TNF-?, IL-1?, and MCP-1 proteins was examined at 1, 2, 4, and 7 days after infection with L. pneumophila (105
CFU). All bars indicate mean ? SE (n ? 6/group). *, P ? 0.05 in comparisons between Il17a?/?Il17f?/?(A/F*) and wild-type (WT) mice. Results are
representative of two independent experiments.
Kimizuka et al.
iai.asm.org Infection and Immunity
is the same pattern observed in the Legionella pneumonia model
BALF of IL-17A/F-deficient mice, a pattern that was consistent
with our real-time PCR and ELISA results indicating a suppres-
sion of CXC chemokines (KC, LIX, and MIP-2). These chemo-
kines, as well as CXCR-2-mediated neutrophil accumulation,
FIG 4 Leukocyte accumulation and gene expression of CXC chemokines in lungs of BALB/c mice infected with Legionella. (A) Total cell numbers and
proportions of different inflammatory cells in the BALF of wild-type and IL-17A/F-deficient (A/F*) mice (BALB/c background) at 1, 2, 4, and 7 days after
mean ? SE (n ? 5/group). Results are representative of three independent experiments.
IL-17 in Legionella Pneumonia
March 2012 Volume 80 Number 3 iai.asm.org 1125
have previously been shown to exert their protective effect during
Legionella infections (40).
Chemokine gene expression in whole-lung tissue could reflect
either altered expression of genes or altered cell composition.
Modest levels of the latter were observed in the BALF of IL-17-
deficient mice. In the future, it will be important to analyze cell
composition in whole-lung tissue in addition to examining
chemokine gene expression in each cell type (e.g., epithelial cells,
neutrophils, and macrophages). The role of epithelial cells, a ma-
Previously (37, 39, 40), we have administered the study ani-
mals one of two types of bacterial dosage: sublethal (105CFU) or
lethal (107CFU). It may be difficult to clearly define our model
(true infection, inflammation, or acute damage) because there is
evaluate host responses, it may be necessary to employ an A/J
mouse or guinea pig model, in which multiplication of Legionella
organisms has been observed. Unfortunately, these are not cur-
There was a 5-day delay between the maximum neutrophil
previously reported that neutrophils play a crucial role during
primary L. pneumophila infection, not via direct killing but by
having more immunomodulatory effects (40). In particular, we
found that, during the acute phase of infection, neutrophils may
be a source of IL-12 in the lungs. This, in turn, drives Th1-type
ication of L. pneumophila at the later phase. However, among the
IL-17A/F-deficient mice in our current study, we did not observe
any variations in the expression of IL-12 and IFN-?. IL-17 may
?-defensin-2, lipocalin 2, and members of the S100 family, from
the effects of these antibacterial factors on L. pneumophila have
been less characterized in in vitro and in vivo pneumonia models.
Th17-driven host defense systems can be positively and/or
activity of Th17 host systems against infectious diseases, the tim-
ing of analysis, infection site, species of the infecting organism,
talk and synergistic interplay between the Th17 and Th1 domains
is plausible as these axes are an integral part of the immune re-
sponse against several different species of intracellular microor-
ganisms (19, 43).
Cumulatively, our results indicate that IL-17 is an important
eral important factors in the immune response, and is associated
with decreases in intrapulmonary bacteria and with increases in
survival rates. Additional research into IL-17 and the Th17 net-
work as a whole is likely to provide new insights into the patho-
genesis of the bacteria and novel therapeutic approaches in the
treatment of Legionella pneumonia.
producing hybridoma. We thank all of the staff and A. Ishizaka for very
helpful suggestions and advice during this project.
This work was supported by JSPS KAKENHI (20790577, 22790958).
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