In inhibit tissue damage.17 Nakijima et al18 have stated

In the present study, GCF level of IL-35
and clinical parameters were evaluated in chronic periodontitis patients with
and without type 2 diabetes before and after SRP. To the best of our knowledge,
this is the first study to compare the GCF IL-35 level before and after SRP in
chronic periodontitis patients with and without type 2 diabetes. A large
number of studies have linked inflammation to the development of insulin
resistance as seen in type 2 diabetes. There is production of inflammatory
cytokines, such as tumor necrosis factor (TNF), interleukins (ILs), and
cytokine-like proteins known as adipokines in type 2 diabetes.15
Homeostasis is maintained by balancing both pro and anti-inflammatory
cytokines. IL-12 is one of
the well studied cytokine family
comprising of both pro and anti-inflammatory cytokines, which include IL-12,
IL-23, IL-27, and IL-35. Out of these ILs, IL-35 has suppressive effect and it
acts as inhibitory cytokine generated by Treg cell populations. IL-35 has a
potential to activate Treg cells especially at high inflammation sites.16 Treg
cells are necessary in the maintenance of immune homeostasis and the prevention
of autoimmune disease.

There is evidence to suggest
that anti?inflammatory Treg cells also play an important role in the
development of periodontal disease and are involved in the subsequent
inflammation and bone resorption. The infiltration of Treg cells into
periodontal tissues reflects their ability to inhibit tissue damage.17 Nakijima et al18 have stated
that patients with chronic periodontitis exhibited increased frequency of T
lymphocytes and CD4 CD25 T cells in the inflammatory infiltrate of gingival
tissues and also exhibited the phenotypic markers of Tregs, such as Foxp3.
These are the potential markers associated with the severity, as well as the
susceptibility of periodontal disease. Various studies have concluded that
periodontal therapy helps in improving HbA1C level.10, 11

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the present study, GCF samples were used for estimation of IL-35 as it is non
invasive, easy to collect, and  it has got
local and systemic biomarkers due to host bacterial interactions.19 The volume
of fluid coming out of the pocket increases together with raising vascular wall
permeability caused by the action of inflammatory mediators. Its composition
changes during the development of inflammation.20,21,22 As a result of inflammation, when GCF leaks from
dilated blood vessels within the gingival connective tissue, this fluid flows
through the inflamed connective tissue, along with the enzymes and other
mediators involved in immune response. This leaked fluid in GCF is an
“inflammatory soup” containing subgingival bacteria and host cells. So, it
offers a great potential as a source of factors that may be associated with
disease activity. According to several researchers, GCF protein
level obtained from the sulcus with clinical symptoms of inflammation is much
higher and has a concentration similar to the concentration of proteins in

In the present study, clinical parameters like plaque index (PI),
gingival index (GI), probing depth (PD) and clinical attachment level (CAL)
were assessed in all the three groups. The values of PI, GI, PD and CAL were
higher in Group II and Group III compared to Group I. There was no significant
difference in PI scores and CAL between Group II and Group III. However after 6
weeks of SRP, there was significant reduction in all the clinical parameters in
both the Groups.

In the present study, the baseline IL-35
values were higher in experimental groups such as group II and group III
compared to the group I (control group). Similar observations were made by Kalburgi et al25, Mitani et al26,
Koseoglu et al27 in their respective studies.

Kalburgi et al
(2013) analyzed the expression profile
of IL-35 mRNA in gingiva of chronic periodontitis and aggressive periodontitis
patients by semiquantitative real time PCR. They observed that IL-35 levels
were higher in chronic periodontitis group compared to the aggressive
periodontitis group and healthy group. The investigators stated that the increased
expression of IL-35 in chronic and aggressive periodontitis suggests its
possible role in pathogenesis of periodontitis. In the present study also,
higher level of IL-35 levels was recorded in CP group compared to healthy
group, thus supporting the findings in the previous study.24

Mitani et al
(2015) conducted a study on expression of IL-35 and IL-17, in gingival tissues
with chronic periodontitis. They found that IL-35 levels were higher in GCF
from chronic periodontitis patients compared to the healthy subjects. They
concluded that IL-35 plays an important role in the pathogenesis of
periodontitis. The findings of our study were consistent with the observations
made by Mitani et al.25

Koseoglu et
al (2015)
assessed the levels of IL-35 in GCF,
saliva, and plasma in periodontal health and disease. IL-35 levels were higher
in chronic periodontitis group compared to gingivitis and healthy group. They
concluded that IL-35 could have an important role in suppressing periodontal
inflammation and maintaining periodontal health. Similar observations were made
in our study.26 This increase in IL-35 levels in chronic periodontitis can be
attributed to its property of anti-inflammatory cytokine. Another study
conducted by Jin et al21 concluded
that increased level of IL?35 plays a
protective role in periodontal disease by maintaining immune system homeostasis
and dampening the inflammatory response.

Thakre et al (2017) compared the GCF level of
IL-35 in patients with chronic gingivitis and chronic periodontitis. They found
that IL-35 levels were higher in chronic gingivitis as
compared with chronic periodontitis group, indicating that the levels of IL-35
decrease with increase in the inflammatory status, so it might play an
important  role in suppressing gingival inflammation
and maintaining periodontal health.23 However, the findings in our
study didn’t support the observations made by Kaustubh Thakre et al.

Various studies validated the potential approach of targeting of
inflammatory mediators as a treatment for type 2 diabetes and support a
causative role for inflammation in the pathogenesis of this disease. This
offers the opportunity to simultaneously targeting several features of the
disease with anti-inflammatory cytokines (either alone or in combination) to
alter the course of the disease. Based on preclinical studies, three anti-inflammatory
approaches have been clinically tested: TNF antagonism, IL-1? antagonism
and salsalate treatment.28, 29, 30

In the present
clinico-biochemical study, a new anti-inflammatory cytokine, IL-35 was
investigated for its role in periodontal inflammation and type 2 diabetes. As
per our literature serach many studies were conducted on IL-35 and its effects
on inflammatory conditions like tuberculosis, laryngeal carcinoma, Hashimotos
thyroiditis and infectious conditions like hepatits. Though there are few
studies describing the effects of IL-35 on type 1 diabetes, no references of
the studies are available on the role of IL-35 in the pathogenesis of
periodontal disease in  type 2 diabetes.
Our main emphasis in this study was the comparative evaluation of the effects
of  SRP on the GCF IL-35 level as
correlated to the clinical parameters.

In the present study,
IL-35 levels were found to be increased with the severity of chronic  periodontitis and the values were decreased
with the resolution of inflammation after the periodontal therapy (SRP). In
group III subjects, the IL-35 levels (110.27± 25.97) were higher compared to the
group II (87.65 ± 33.52) which depicts its inflammatory component along with
altered host immune response. Another important observation made in this study
was that the IL-35 levels were not reduced to a great extent after periodontal
therapy in group III (83.26 ± 18.77) subjects compared to group II (47.04 ±
18.38), which suggests that the anti-inflammatory cytokines levels have a role
in the pathogenesis of periodontitis and type 2 diabetes.

The results
of the present study indicate that IL?35 expression increases with progression
of chronic periodonititis, which may help to attenuate its progression. More
specifically, gram?negative anaerobic bacteria at the bottom of periodontal
pockets may invade epithelial cells and hide in host cells, aggravating the
destruction of periodontal tissue; they can potentially also invade endothelial
cells and access the blood circulation to stimulate a host immune response and
cause systemic inflammation. IL?35, as a negative regulator of immune factors,
may slow or inhibit the development of periodontal disease and thus, indirectly
slows down the systemic disease process.30,31,32


On the basis of results
in the present study, it was concluded that the GCF level of IL-35 can be used
as a reliable indicator for the severity of periodontal disease. As IL?35 is a relatively recently
identified cytokine which has not been studied in many disease models, further
studies are required to prove this. Since the parameters investigated in the
present study are few, it is unclear whether IL?35 enhances or antagonizes the
effects of other cytokines or immune cells in CP with   diabetes. In future studies, it will be
necessary to increase the sample size and a greater number of parameters
to understand the role of IL?35 in chronic periodontitis  with diabetes and its use in the treatment of
chronic periodontitis.