J Periodontol • November 2012

The Gingival Crevicular Fluid Levels

of Interleukin-11 and Interleukin-17
in Patients With Aggressive Periodontitis
xak,† Recep Sütc
Zuhal Yetkin Ay,* Gülin Yılmaz,* Muhsin Özdem,* Havva Koc xü,† Ersin Uskun,‡
x,* and Fatma Yesxim Kırzıo
Mine Öztürk Tonguc glu*

Background: The balance (ratio) of anti-inflammatory and

proinflammatory cytokines is thought to play an important
role in the pathogenesis of chronic periodontitis. Moreover,
the imbalance of anti-inflammatory/proinflammatory cyto-
kines may modulate disease progression in aggressive peri-
odontitis (AgP). This study aims to investigate the levels of
interleukin (IL)-11 and IL-17 and their ratio in gingival crevic-

A
ggressive periodontitis (AgP) is a
ular fluid (GCF) in patients with AgP. particular type of periodontal tis-
Methods: This study included 20 patients with generalized sue disease, aggressive in nature
AgP (GAgP) and 18 healthy controls (HC). For each patient, regarding progression rate and pattern
the values of clinical parameters, such as gingival index, pla- of tooth-supporting tissues, and leads to
que index, probing depth, and clinical attachment level, were loss of teeth. Early age of onset is one of
recorded. Levels of IL-11 and IL-17 in GCF samples were eval- the main characteristics of AgP.1 Patients
uated using enzyme-linked immunosorbent assay. The values with AgP are otherwise clinically healthy.
of clinical parameters, cytokine levels, and the ratios of cyto- The amount of microbial deposit is in-
kines were evaluated. consistent with disease severity; more-
Results: The values of all the clinical parameters were sig- over, the presence of familial aggregation
nificantly higher in the GAgP group than in the HC group has been reported.2
(P <0.001). The total amount and concentration of IL-11 and In periodontal disease, cytokines be-
the concentration of the IL-17 and IL-11/IL-17 ratio were sig- have as components of a ‘‘network’’ in
nificantly lower in the GAgP group than in the HC group the immune response against bacteria and
(P <0.001). The total amount of IL-17 was not significantly dif- their virulence factors. In this network,
ferent between the groups (P = 0.317) cytokines are considered to play an im-
Conclusions: The IL-11/IL-17 ratio was decreased in the portant role in the initiation, progression,
GAgP group because of the decreased IL-11 levels. The and host modulation of periodontal in-
IL-11/IL-17 axis and the link between IL-17 and neutrophil flammation. The relative importance of
function disorders in AgP should be investigated to clarify T-helper (Th)1 and Th2 subsets and the
the role of the IL-11/IL-17 axis and its balance and imbalance nature of their cytokine synthesis in peri-
in the pathogenesis of AgP. J Periodontol 2012;83:1425-1431. odontal inflammation have also been in-
vestigated. It is known that, in a healthy
KEY WORDS
immune response, Th1 and Th2 cytokine
Aggressive periodontitis; cytokines; gingival crevicular fluid; profiles are in equilibrium. Disruption of
periodontal diseases. this homeostasis results in inflammatory/
immune disease.3 In recent years, another
* Department of Periodontology, Faculty of Dentistry, Süleyman Demirel University, subset of Th cells, Th17 cells, have re-
Isparta, Turkey.
† Department of Biochemistry, Faculty of Medicine, Süleyman Demirel University. ceived great attention because of their
‡ Department of Public Health, Faculty of Medicine, Süleyman Demirel University. ability to produce a proinflammatory
cytokine, interleukin (IL)-17.4-6 Polymor-
phonuclear cells have also been reported
to produce IL-17.7,8 The production and
development of Th17 cells is dependent on
IL-6, IL-23, and transforming growth

doi: 10.1902/jop.2012.110585

1425
The GCF IL-11, IL-17 Levels in Aggressive Periodontitis
factor-b; IL-17 negatively regulates Th1-mediated
response in the presence of IL-23.9 Moreover, Th17
cells can be converted to Th1 or Th2 cells under the
influence of IL-12 or IL-4.10 IL-17 activates fibroblasts
and endothelial cells to increase their secretion of IL-6
in the presence of tumor necrosis factor-alpha (TNF-
a).11,12 IL-17 exacerbates periodontal disease by acti-
vating the gingival fibroblasts to produce inflammatory
mediators.13 Similar to its role in chronic periodontitis
(CP), IL-17 may play an important role in AgP because
of the functional impairment of polymorphonuclear
leukocytes and because of the association of Th17
pathways with the recruitment of neutrophils, which
results in enhanced inflammation and bone resorption.
Another immunoregulatory cytokine, IL-11, is a
pleiotrophic cytokine produced by various stromal
cells, including fibroblasts, epithelial cells, and osteo-
blasts.14 IL-11 has many biologic activities and func-
tions, e.g., in hematopoiesis, in immune response, in
the nervous system, and in bone metabolism.15 IL-11
has been reported to have anti-inflammatory proper-
ties and a Th2-polarizing effect and therefore can be
used for the treatment of Th1-predominant inflam-
matory disease by exerting a modulator effect on naive
T cells16 and on the expression of proinflammatory
cytokines, such as IL-1b, TNF-a, IL-6, IL-12, and nitric
oxide by macrophages.17-19 Furthermore, IL-6 down-
regulates the expression of IL-11 in cultured osteoblast-
like cells, and it has also been also reported that IL-6
expression is significantly upregulated by IL-17 in skin
and synovial fibroblast cultures.11,12
Briefly, a slight imbalance of cytokine production
may affect the induction of bone and collagen de-
struction in periodontal disease.20 It is therefore im-
portant to determine the shared characteristics (or
similarities) and unique characteristics (or differen-
ces) of CP and AgP in terms of the cytokine balance
and imbalance to develop new treatment strategies.
The hypothesis of the present study is that the
ratio of IL-11/IL-17 (anti-inflammatory and proin-
flammatory cytokines, respectively) is altered in AgP,
with decreased IL-11 and increased IL-17 levels and
decreased IL-11/IL-17 ratio compared with healthy
controls. Thus, the levels of IL-11 and IL-17 and their
ratio were investigated in patients with generalized
AgP (GAgP) and were compared to those in peri-
odontally healthy controls (HC).
MATERIALS AND METHODS
The present study was conducted in accordance with
the Good Clinical Practice and ethical standards laid
down in Version VI (2002) of the Declaration of Hel-
sinki and its amendments in Tokyo and Venice. The
protocol was approved by the Ethics Committee of
Süleyman Demirel University Faculty of Medicine
(meeting date, June 1, 2006; number of meeting/
1426
Volume 83 • Number 11
decision, 04/09). The nature of the study was ex-
plained in detail to each patient, and informed con-
sent was obtained. The study was conducted from
June to December 2006.
The patients in the GAgP group were selected
based on previously described criteria.21 The diagnosis
of GAgP required familial aggregation, with ‡1 other
family member presenting with or having a history of
periodontal disease. The patients were diagnosed
with GAgP if they had a minimum of 5 mm attach-
ment loss (AL) in ‡1 site in >8 teeth, three of which were
other than first molars and incisors and had radio-
graphic evidence of advanced alveolar bone loss. In
addition, an HC group with periodontally healthy
patients having a mean gingival index (GI) < 1 and
a mean probing depth (PD) £ 3 mm but with no sites
having a mean AL ‡ 3 mm except for the presence of
mucogingival problems was constituted.
None of the patients were former smokers or current
smokers. In addition, none of the patients had any
known systemic disorder or had used prescribed anti-
biotics and/or anti-inflammatory medications within
3 months before the study. Patients and control in-
dividuals with active infectious diseases, such as hep-
atitis, human immunodeficiency virus infection, and
tuberculosis, or those being chronically treated with
medications (phenytoin, cyclosporine A, or calcium
channel blockers) as well as women who were lactating
or pregnant were excluded from the study.
Periodontal Examination
For each patient, GI,22 plaque index (PI),23 PD, and
clinical attachment level (CAL) were recorded. The
values of periodontal variables corresponding to
the gingival crevicular fluid (GCF) sampling areas
were recorded as site (e.g., PDs). The clinical exam-
ination was performed by the same examiner (ZYA),
and the examination was calibrated before the study.
Analysis of Intra-Examiner Reproducibility
The reproducibility of the data collected by the ex-
aminer (ZYA) was assessed by performing clinical
periodontal data collection in five patients. Each
patient was assessed twice during one visit over a 1-
hour interval. The second set of recordings was
masked to the first assessment. The reproducibility of
the data collection was determined by calculating
the percentage of sites examined in which the scores
were reproduced precisely or to an accuracy of 1 mm
for each site. Assessment of the mean difference in
the scores (with 85% accuracy) between visits indicated
that there was no systematic bias in measurement.
GCF Sampling
Clinical measurements were recorded, and GCF sam-
pling sites were selected 1 week before sampling. The
GCF samples were collected from four non-adjacent
J Periodontol • November 2012
sites that fulfilled the criteria (GAgP, PD ‡ 4 mm; HC,
PD £ 3 mm). After isolating the tooth with a cotton roll,
supragingival plaque was removed using curets§ with-
out touching the marginal gingiva. The crevicular site
was then dried gently with an air syringe. A saliva
ejector and cotton rolls were used to avoid salivary
contamination. GCF collection stripsi were held
within the gingival sulci for 30 seconds at the sam-
pling site of each patient. If there was visible con-
tamination with blood, the strips were discarded, and
other sites fulfilling the same criteria were selected.
The strips were transferred to the calibrated GCF
volume measurement device¶ located at the side of
the chair. After the measurement, the strips were
transferred to plastic vials and sealed with parafilm to
avoid evaporation. The samples were stored at -80C
until assayed.
IL-11 and IL-17 Analysis
After thawing, the strips were eluted by centrifugation
(3,000 · g, 4C, 15 minutes) with 700 µL Hank’s
balanced salt solution containing 0.5% bovine serum
albumin. Enzyme-linked immunosorbent assays
(ELISA) were used for quantitative detection of IL-11#
and IL-17.** Briefly, IL-11 and IL-17 present in the
sample were bound to anti-IL-11 and anti-IL-17
monoclonal coating antibody absorbed to the mi-
crowells. Next, secondary polyclonal antibodies were
added, and, after incubation, colored products were
formed in proportion to the amount of IL-11 and IL-17
present in the sample. To determine the cytokine level
in each sample, standard curve plots of pure IL-11 and
IL-17 were used. The sensitivity of the IL-11 ELISA kit
was reported to be <10 pg/mL, and the assay range was
0 to 1,600 pg/mL. The minimum detectable concen-
tration was estimated to be 2 pg/mL for IL-17, and no
significant cross-reactivity or interference of the ELISA
kit was observed for IL-17 (the sensitivity). The reactions
were measured at 450 nm. The total amount of IL-11
and IL-17 was determined in picograms. The concen-
trations of the cytokines were corrected for GCF vol-
ume and were expressed in picograms per milliliters.
Statistical Analyses
Continuous variables are presented as median, min-
imum, and maximum, whereas categorical variables
are presented as frequencies. Because the distribution
of the data was not homogeneous (determined using
the Kolmogorov-Smirnov test), non-parametric tests
were used for the statistical analysis and evaluation
of the data. Analyses of differences between the
two groups were performed using the Mann-Whitney
U test. All reported P values are based on two-sided
tests and compared with a significance level of 5%.
Correlations between clinical periodontal variables
and GCF variables were tested by calculating the
Yetkin Ay, Yılmaz, Özdem, et al.
Pearson r correlation coefficients. A software pro-
gram†† was used for all the statistical calculations.
RESULTS
Clinical Periodontal Variables
The values of clinical periodontal and demographic
variables and the significant differences between the
GAgP group and the HC group are presented in Table 1.
All the clinical variables were found to be significant-
ly higher in the GAgP group than in the HC group
(P <0.001).
GCF Variables
The GCF variables are shown in Table 2. The total
amount of IL-11 was significantly lower in the GAgP
group than in the HC group (mean – SD, 4.28 – 2.90
versus 16.71 – 8.35 pg), similar to the concentration of
IL-11 (1.61 – 1.83 versus 17.69 – 10.43 pg/mL) and
concentration of IL-17 (4.53 – 2.77 versus 15.16 –
6.43 pg/mL) (P values <0.001). However, the total
amount of IL-17 in the GAgP group was not signifi-
cantly different from that in the HC group (13.81 – 4.60
versus 14.59 – 3.49 pg) (P = 0.317).
Correlations
The correlations between the GCF variables (the total
amount and the concentrations of IL-11 and IL-17)
and the clinical variables at the sampling sites were
investigated. Significant correlations were only ob-
served between the total amount of IL-11 and the GI
at the sampling sites and between the total amount of
IL-11 and the PI at the sampling sites (r = -0.654 and
r = -0.632; P = 0.008 and P = 0.002, respectively).
DISCUSSION
To the best of our knowledge, this is the first study
to investigate the levels of IL-11 and IL-17 and their
ratio in the GCF of patients with GAgP. The total
amount and concentration of IL-11 and the concen-
tration of IL-17 in GCF were significantly lower in the
GAgP group than in the HC group.
There are some studies that have investigated the
levels of IL-11 in GCF or in gingival tissue of peri-
odontitis patients.24-26 In a previous study,26 it was
observed that the total amount and concentration
of IL-11 were significantly decreased in the patients
with CP who had the deeper PD in the sampling sites
compared with those of the other groups (CP with
a shallower PD and HC). These results are in accor-
dance with the results obtained by Johnson et al.,24
who reported a decrease in IL-11 concentration in
gingival tissues adjacent to periodontal pockets that
§ Gracey curets, Hu-Friedy, Chicago, IL.
i PerioPaper, Oraflow, Smithtown, NY.
¶ Periotron 8000, Oraflow.
# US Biologic, Swampscott, MA.
** Biosource, Camarillo, CA.
†† SPSS 9.0, IBM, Chicago, IL.
1427
The GCF IL-11, IL-17 Levels in Aggressive Periodontitis Volume 83 • Number 11

Table 1.
Characteristics and Periodontal Parameter Values of the Groups in the Whole-Mouth
and Sampling Sites [median (minimum - maximum)]

Parameters/Groups GAgP (n = 20) HC (n = 18) P*

Age 33.50 (24.00 to 47.00) 27.00 (25.00 to 48.00) <0.001

Male/female 6/14 6/12
GI 2.43 (1.85 to 3.04) 0.29 (0.00 to 1.23) <0.001

PI 2.20 (1.54 to 2.88) 0.29 (0.08 to 1.59) <0.001

PD (mm) 4.44 (3.66 to 5.97) 2.16 (1.09 to 3.12) <0.001
CAL (mm) 4.99 (4.16 to 7.22) 2.27 (1.23 to 3.18) <0.001
GI-s 2.50 (0.07 to 3.00) 0.00 (0.00 to 1.00) <0.001

PI-s 2.27 (0.75 to 3.00) 0.07 (0.00 to 1.50) <0.001

PD-s (mm) 6.90 (5.00 to 10.83) 1.50 (0.07 to 2.50) <0.001
CAL-s (mm) 7.09 (5.00 to 11.50) 1.50 (0.07 to 2.50) <0.001
s = sampling site.
* Significance level at P <0.05; Mann-Whitney U test.

Table 2.
GCF Volume and Total Amount and Concentrations of the Cytokines IL-11 and IL-17
(median [minimum - maximum])

Parameters/Groups GAgP (n = 20) HC (n = 18) P*

GCF (mL) 3.80 (1.26 to 6.32) 1.01 (0.56 to 1.61) <0.001

IL-11 (pg) 1.05 (0.25 to 7.66) 16.68 (6.98 to 43.28) <0.001

IL-11 (pg/mL)/30 seconds 3.05 (0.55 to 7.86) 13.61 (5.95 to 39.34) <0.001
IL-17 (pg) 12.84 (6.76 to 26.25) 14.06 (6.76 to 21.37) 0.317
IL-17 (pg/mL)/30 seconds 3.80 (1.08 to 11.90) 12.09 (9.00 to 30.24) <0.001

IL-11/IL-17 0.24:1 1.09:1 <0.001

* Significance level at P <0.05; Mann-Whitney U test.

were deeper than 6 mm. They suggested that this
decrease may result in the deficiency of the pro-
tective role of IL-11 in periodontal lesions. Yücel
et al.25 have also reported decreased levels of IL-11
in GCF of patients with CP compared with those in
the GCF of gingivitis patients and healthy controls.
Similar to the results obtained from CP patients, our
present study shows that the total amount and con-
centration of IL-11 were decreased in samples from
the GAgP group compared with those in the samples
from the HC group. The findings of our previous study
and the present study indicate that IL-11, because
of its anti-inflammatory properties, plays a protective
role against periodontal disease and the pathogen-
esis of AgP. In addition, the significant negative
correlation between GI in the sampling site and the
total amount of IL-11 should be taken into account
while assessing the anti-inflammatory role of IL-11.
Some authors have described the role of IL-11 in
controlling the inflammatory response in periodontal
disease, psoriasis, and rheumatoid arthritis and men-
tioned IL-11 therapy.18,27 It has been shown that IL-11
induces osteoblastic differentiation and bone forma-
tion in vivo and in vitro.28 These results have led us
to consider that IL-11 may be acting as a key mediator
in preventing the progressive inflammation from
leading to periodontal tissue breakdown in GAgP
patients, which is similar to that observed in CP

1428
J Periodontol • November 2012
patients. Unfortunately, no studies have evaluated
GCF and/or serum IL-11 in GAgP patients that allow
us draw comparative conclusions.
Recent studies have focused on the role of IL-17
in inflammatory diseases, such as rheumatoid ar-
thritis, asthma, cancer, allergic diseases, and other
immune-mediated diseases, and in organ transpla-
ntation and rejection processes.6 The relatively short
time after discovery and the cytokine profile of
Th17 cells were primarily investigated in periodon-
tal diseases because of the similarities to the above-
mentioned diseases in terms of inflammatory processes.
Studies using tissue biopsies have shown the presence
of IL-17 in inflamed gingival tissues.13,24,29-31 Allam
et al.32 have recently reported that IL-17 plays a major
role, especially at severely inflamed sites of CP, such
as the lower region of the lesions, whereas other sites,
such as the coronal region, are characterized by both
reduced Th17 infiltration and reduced inflammation.
Thus, it is tempting to speculate that IL-17 plays a role
mainly in the destruction of periodontal tissue, which
increases the severity of CP. In addition, immunocyto-
chemical studies have reported 6.2-fold higher posi-
tively stained cells for IL-17 in gingival tissues from
patients with periodontitis.33 Culture supernatant frac-
tions were also investigated for the presence of IL-17,
and IL-17 protein and mRNA positivity was re-
ported.32,34 The expression of IL-17 was also observed
in the alveolar bone of CP patients.35
GCF was also analyzed for the presence and the
level (total amount and/or concentration) of IL-17.
In their previous study, the current authors evaluated
IL-17 levels in GCF of CP patients and observed
results similar to those in the present study, such as
the lower total amount of IL-17 in deeper pockets
than in shallower pockets of CP patients and in the
periodontal sulcus of the healthy controls.26 In the
present study, the total amount of IL-17 is not
significantly different between the GAgP and HC
groups; however, significantly lower IL-17 concen-
trations were observed in the GAgP group than in
the HC group. This low concentration of IL-17, which
was not observed in the study of Vernal et al.,29 might
be attributable to its degradation in GCF, a relatively
lower level of IL-17 in GCF, a heterogeneous re-
sponse because of racial variation, or a combination
of some or all of these factors.13,36 In addition, the de-
creased concentration might be the result of a signifi-
cantly higher volume of GCF in the GAgP patients
when the total amount of IL-17 was considered.
Schenkein et al.37 have recently reported elevated
serum IL-17 levels in GAgP patients compared with
those in localized AgP patients and healthy controls.
They suggested ‘‘an altered systemic response to oral
bacterial antigens’’ in this patient group to explain the
elevated systemic level of IL-17 in AgP patients. They
Yetkin Ay, Yılmaz, Özdem, et al.
speculated that this elevated serum IL-17 level may
indicate an autoimmune response when combined
with evidence that AgP is familial and is likely to have
a significant component of genetic risk. Zhao et al.38
reported that non-surgical treatment of patients with
CP might decrease the expression of Th17-related
cytokines IL-17 and IL-21 and Th1-related cytokine
interferon-g (IFN-g) but increase the expression of
Th2-related cytokine IL-4. Duarte et al.39 evaluated
the serum IL-17 levels with the other cytokines (IL-4,
IL-23, TNF-a, and IFN-g) in GAgP and CP patients
before and after non-surgical periodontal therapy.
They reported similar results to those obtained by
Schenkein et al.37 in terms of higher serum levels of
IL-17 GAgP patients compared with those in gener-
alized CP patients and healthy controls and showed
that the level of IL-17 was decreased after the peri-
odontal therapy, which was similar to the results ob-
tained by Zhao et al.38 Schenkein et al.37 concluded
that the elevated level of IL-17 is because of the
proinflammatory nature of IL-17 and its ability to in-
duce the production of other proinflammatory medi-
ators, including TNF-a. Conversely, Özcxaka et al.40
have reported similar plasma concentrations of IL-17
in CP patients and healthy controls. The current au-
thors agree with the comments of Özcxaka et al.40 that
CP differs from AgP in many respects, such as genetic
factors, progression rate, and susceptibility factors. In
addition, inflammatory mediators seem to play a dual
role in the disease, contributing to the control of
periodontal infection while triggering tissue destruc-
tive pathways.41 The lower IL-17 concentrations in
GCF in the present study should be evaluated with this
point in mind in GAgP patients for additional studies.
It is known that patients with AgP have reduced
neutrophil chemotaxis,42,43 impaired phagocytosis,
or both.44,45 It has been reported that the effect of
IL-17 in local inflammation might be attributable to
its effect of inducing cells to release proinflammatory
cytokines and recruiting neutrophils.46 Yu et al.46
have attributed an essential role for IL-17 in pre-
venting pathogen-initiated bone destruction via the
mobilization of neutrophils. In addition, IL-17 could
enhance the activity of proteolytic enzymes, such as
neutrophil protease, myeloperoxidase, and the ex-
pression of cytokines and chemokines, which facili-
tate the development of inflammation.33 Studies
investigating this link between IL-17 and neutrophil
function disorders in AgP should be conducted in
larger AgP populations to clarify the pathogenesis
of AgP related to IL-17.
The IL-11/IL-17 axis has not been investigated ex-
tensively in the pathogenesis of periodontitis. How-
ever, the balance, imbalance, and axis of IL-11 and
IL-17 in inflammatory diseases, such as rheumatoid ar-
thritis, inflammatory bowel disease, temporomandibular
1429
The GCF IL-11, IL-17 Levels in Aggressive Periodontitis
joint disorders, airway neutrophilia, asthma, and so on,
has attracted a great deal of attention recently.47-49 These
studies have evaluated IL-11 and IL-17 as proin-
flammatory cytokines and have reported that they
are related to bone destruction in rheumatoid ar-
thritis and temporomandibular joint disorders.47-49
Kawaguchi et al.49 have suggested that IL-11 could
be induced by IL-17 in bronchial epithelial cells.
Except for general immunologic pathways, these
diseases are quite different in terms of location,
pathogenesis, and etiology when compared with
periodontitis, especially AgP. However, the results of
the present study were supported by the previous
study26 and other studies in the field of periodon-
tology,24,25 which have shown that levels of IL-11
and/or IL-17 are decreased in deeper periodontal
pockets. The positive correlations between the cy-
tokine concentrations in the present study support
this possible link between the two cytokines. The
integral role of IL-6 in upregulating the expression of
IL-17 and downregulating the expression of IL-
1111,12 should also be investigated in AgP, as well as
IL-1 and TNF-a, the other key cytokines in peri-
odontal disease, and evidenced to be induced by IL-
17 to be produced by macrophages.33 Kawaguchi
et al.49 reported that IL-17 in airway inflammation
is likely mediated by the induction of IL-11. IL-17
was reported to be an inducer of IL-11 and induces
airway remodeling and inflammation either alone or
in combination with Th2 cytokines.49
CONCLUSIONS
The IL-11/IL-17 ratio was decreased in patients with
GAgP because of the decreased levels of IL-11. The
IL-11/IL-17 axis should be investigated in AgP and
also in CP with respect to their relationship with each
other and with other key cytokines (IL-1, IL-6, and
TNF-a). Most importantly, the signaling pathway of
the two cytokines in terms of the expression patterns
should be investigated to clarify the interaction of
IL-11 and IL-17 in the pathogenesis of AgP.
ACKNOWLEDGMENTS
This study was financially supported by Scientific In-
vestigation Management Unit Project 1206-m-05
(Süleyman Demirel University, Isparta, Turkey). The
authors report no conflicts of interest related to this
study.
REFERENCES
1. Kinane DF. Periodontitis modified by systemic factors.
Ann Periodontol 1999;4:54-64.
2. Tonetti MS, Mombelli A. Early-onset periodontitis. Ann
Periodontol 1999;4:39-53.
3. Houri-Haddad Y, Wilensky A, Shapira L. T-cell pheno-
type as a risk factor for periodontal disease. Periodontol
2000 2007;45:67-75.
1430
Volume 83 • Number 11
4. Kramer JM, Gaffen SL. Interleukin-17: A new paradigm
in inflammation, autoimmunity, and therapy. J Peri-
odontol 2007;78:1083-1093.
5. Lubberts E. IL-17/Th17 targeting: On the road to
prevent chronic destructive arthritis? Cytokine 2008;
41:84-91.
6. Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in
human disease. Immunol Rev 2008;223:87-113.
7. Witowski J, Pawlaczyk K, Breborowicz A, et al. IL-17
stimulates intraperitoneal neutrophil infiltration through
the release of GRO alpha chemokine from mesothelial
cells. J Immunol 2000;165:5814-5821.
8. Ferretti S, Bonneau O, Dubois GR, Jones CE, Trifilieff
A. IL-17, produced by lymphocytes and neutrophils, is
necessary for lipopolysaccharide-induced airway neu-
trophilia: IL-15 as a possible trigger. J Immunol 2003;
170:2106-2112.
9. Zelante T, De Luca A, Bonifazi P, et al. IL-23 and the
Th17 pathway promote inflammation and impair anti-
fungal immune resistance. Eur J Immunol 2007;37:
2695-2706.
10. Lexberg MH, Taubner A, Förster A, et al. Th memory
for interleukin-17 expression is stable in vivo. Eur J
Immunol 2008;38:2654-2664.
11. Katz Y, Nadiv O, Beer Y. Interleukin-17 enhances tumor
necrosis factor alpha-induced synthesis of interleukins
1,6, and 8 in skin and synovial fibroblasts: A possible
role as a ‘‘fine-tuning cytokine’’ in inflammation pro-
cesses. Arthritis Rheum 2001;44:2176-2184.
12. Nakchbandi IA, Mitnick MA, Masiukiewicz US, Sun BH,
Insogna KL. IL-6 negatively regulates IL-11 production
in vitro and in vivo. Endocrinology 2001;142:3850-
3856.
13. Takahashi K, Azuma T, Motohira H, Kinane DF, Kitetsu
S. The potential role of interleukin-17 in the immuno-
pathology of periodontal disease. J Clin Periodontol
2005;32:369-374.
14. Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6
family of cytokines and gp130. Blood 1995;86:1243-
1254.
15. Du X, Williams DA. Interleukin-11: review of molecular,
cell biology, and clinical use. Blood 1997;89:3897-
3908.
16. Curti A, Ratta M, Corinti S, et al. Interleukin-11 induces
Th2 polarization of human CD4(+) T cells. Blood 2001;
97:2758-2763.
17. Redlich CA, Gao X, Rockwell S, Kelley M, Elias JA.
IL-11 enhances survival and decreases TNF production
after radiation-induced thoracic injury. J Immunol 1996;
157:1705-1710.
18. Trepicchio WL, Wang LL, Bozza M, Dorner AJ. IL-11
regulates macrophage effector function through the
inhibition of nuclear factor-kappaB. J Immunol 1997;
159:5661-5670.
19. Seymour GJ, Gemmell E. Cytokines in periodontal
disease: Where to from here? Acta Odontol Scand
2001;59:167-173.
20. Honda T, Domon H, Okui T, Kajita K, Amanuma R,
Yamazaki K. Balance of inflammatory response in
stable gingivitis and progressive periodontitis lesions.
Clin Exp Immunol 2006;144:35-40.
21. Armitage GC. Development of a classification system
for periodontal diseases and conditions. Ann Periodon-
tol 1999;4:1-6.
22. Löe H, Silness J. Periodontal disease in pregnancy. I.
Prevalence and severity. Acta Odontol Scand 1963;21:
533-551.
J Periodontol • November 2012
23. Silness J, Löe H. Periodontal disease in pregnancy. II.
Correlation between oral hygiene and periodontal
condition. Acta Odontol Scand 1964;22:121-135.
24. Johnson RB, Wood N, Serio FG. Interleukin-11 and
IL-17 and the pathogenesis of periodontal disease.
J Periodontol 2004;75:37-43.
25. Yücel OO, Berker E, Garibo glu S, Otlu H. Interleukin-11,
interleukin-1b, interleukin-12 and the pathogenesis of
inflammatory periodontal diseases. J Clin Periodontol
2008;35:365-370.
26. Yetkin Ay Z, Sütcxü R, Uskun E, Bozkurt FY, Berker E.
The impact of the IL-11:IL-17 ratio on the chronic peri-
odontitis pathogenesis: A preliminary report. Oral Dis
2009;15:93-99.
27. Martuscelli G, Fiorellini JP, Crohin CC, Howell TH. The
effect of interleukin-11 on the progression of ligature-
induced periodontal disease in the beagle dog. J Peri-
odontol 2000;71:573-578.
28. Suga K, Saitoh M, Kokubo S, et al. Synergism between
interleukin-11 and bone morphogenetic protein-2 in
the healing of segmental bone defects in a rabbit
model. J Interferon Cytokine Res 2004;24:343-349.
29. Vernal R, Dutzan N, Chaparro A, Puente J, Antonieta
Valenzuela M, Gamonal J. Levels of interleukin-17 in
gingival crevicular fluid and in supernatants of cellular
cultures of gingival tissue from patients with chronic
periodontitis. J Clin Periodontol 2005;32:383-389.
30. Lester SR, Bain JL, Johnson RB, Serio FG. Gingival
concentrations of interleukin-23 and -17 at healthy
sites and at sites of clinical attachment loss. J Peri-
odontol 2007;78:1545-1550.
31. Ohyama H, Kato-Kogoe N, Kuhara A, et al. The
involvement of IL-23 and the Th17 pathway in peri-
odontitis. J Dent Res 2009;88:633-638.
32. Allam JP, Duan Y, Heinemann F, et al. IL-23-producing
CD68(+) macrophage-like cells predominate within
an IL-17-polarized infiltrate in chronic periodontitis
lesions. J Clin Periodontol 2011;38:879-886.
33. Beklen A, Ainola M, Hukkanen M, Gürgan C, Sorsa T,
Konttinen YT. MMPs, IL-1, and TNF are regulated by
IL-17 in periodontitis. J Dent Res 2007;86:347-351.
34. Ito H, Honda T, Domon H, et al. Gene expression anal-
ysis of the CD4+ T-cell clones derived from gingival
tissues of periodontitis patients. Oral Microbiol Immunol
2005;20:382-386.
35. Cardoso CR, Garlet GP, Crippa GE, et al. Evidence of
the presence of T helper type 17 cells in chronic lesions
of human periodontal disease. Oral Microbiol Immunol
2009;24:1-6.
36. Pradeep AR, Hadge P, Chowdhry S, Patel S, Happy D.
Exploring the role of Th1 cytokines: Interleukin-17
and interleukin-18 in periodontal health and disease.
J Oral Sci 2009;51:261-266.
37. Schenkein HA, Koertge TE, Brooks CN, Sabatini R,
Purkall DE, Tew JG. IL-17 in sera from patients with
aggressive periodontitis. J Dent Res 2010;89:943-947.
38. Zhao L, Zhou Y, Xu Y, Sun Y, Li L, Chen W. Effect of
non-surgical periodontal therapy on the levels of Th17/
Yetkin Ay, Yılmaz, Özdem, et al.
Th1/Th2 cytokines and their transcription factors in
Chinese chronic periodontitis patients. J Clin Periodon-
tol 2011;38:509-516.
39. Duarte PM, da Rocha M, Sampaio E, et al. Serum levels
of cytokines in subjects with generalized chronic and
aggressive periodontitis before and after non-surgical
periodontal therapy: A pilot study. J Periodontol 2010;
81:1056-1063.
40. Ozcxaka Ö, Nalbantsoy A, Buduneli N. Interleukin-17
and interleukin-18 levels in saliva and plasma of pa-
tients with chronic periodontitis. J Periodontal Res
2011;46:592-598.
41. Garlet GP, Cardoso CR, Campanelli AP, et al. The dual
role of p55 tumour necrosis factor-alpha receptor
in Actinobacillus actinomycetemcomitans-induced ex-
perimental periodontitis: Host protection and tissue
destruction. Clin Exp Immunol 2007;147:128-138.
42. Offenbacher S, Scott SS, Odle BM, Wilson-Burrows C,
Van Dyke TE. Depressed leukotriene B4 chemotactic
response of neutrophils from localized juvenile peri-
odontitis patients. J Periodontol 1987;58:602-606.
43. Palmer GD, Watts TL, Addison IE. A skin window study
of neutrophil migration in subjects with localized juve-
nile periodontitis. J Clin Periodontol 1993;20:452-456.
44. Kimura S, Yonemura T, Hiraga T, Okada H. Flow
cytometric evaluation of phagocytosis by peripheral
blood polymorphonuclear leucocytes in human peri-
odontal diseases. Arch Oral Biol 1992;37:495-501.
45. Eick S, Pfister W, Sigusch B, Straube E. Phagocytosis of
periodontopathogenic bacteria by crevicular granulo-
cytes is depressed in progressive periodontitis. Infec-
tion 2000;28:301-304.
46. Yu JJ, Ruddy MJ, Wong GC, et al. An essential role for
IL-17 in preventing pathogen-initiated bone destruc-
tion: Recruitment of neutrophils to inflamed bone re-
quires IL-17 receptor-dependent signals. Blood 2007;
109:3794-3802.
47. Kaneyama K, Segami N, Sato J, Nishimura M, Yoshimura
H. Interleukin-6 family of cytokines as biochemical
markers of osseous changes in the temporomandibular
joint disorders. Br J Oral Maxillofac Surg 2004;42:246-
250.
48. Juarranz Y, Abad C, Martinez C, et al. Protective effect
of vasoactive intestinal peptide on bone destruction
in the collagen-induced arthritis model of rheumatoid
arthritis. Arthritis Res Ther 2005;7:R1034-R1045.
49. Kawaguchi M, Fujita J, Kokubu F, et al. IL-17F-induced
IL-11 release in bronchial epithelial cells via MSK1-
CREB pathway. Am J Physiol Lung Cell Mol Physiol
2009;296:L804-L810.
Correspondence: Dr. Zuhal Yetkin Ay, Department of
Periodontology, Faculty of Dentistry, Süleyman Demirel
xünür, Isparta, Turkey. Fax: 90-246-
University, 32260, C
2370607; e-mail: zuhalyetkin@yahoo.com.
Submitted October 3, 2011; accepted for publication
January 2, 2012.
1431
Copyright of Journal of Periodontology is the property of Wiley-Blackwell and its content
may not be copied or emailed to multiple sites or posted to a listserv without the copyright
holder's express written permission. However, users may print, download, or email articles for
individual use.