Table 1 General characteristics and main outcomes of the included studies

Kamiya 2020 [42]

Invitro Study

In this study, IL-35 and RANKL induced osteoclastogenesis synergistically

Osteoclastogenesis activity

Shindo 2019 [41]

Invitro study

Results of this study indicate that IL-35 plays a role in regulating the progression of periodontitis by inhibiting inflammatory cytokine (IL-6 and IL-8) production

Anti-inflammatory activity

Cafferata 2020 [43]

Animal Study (locally & systemically administrated IL-35)

IL-35 inhibited alveolar bone resorption in periodontitis mice

IL-35 inhibited alveolar bone resorption and this inhibition was closely associated with modulation of the periodontal Th17/Treg imbalance

Anti-inflammatory activity

Cai 2017 [45]

Cross- sectional (GCF and Serum samples)

The study confirmed the presence of high levels of IL-35 on GCF (or blood) of CP patients. Moreover, high concentrations of IL-35 on GCF may relate to the levels of them on blood

Elevated IL-35-related sCD14 is associated with the severity of periodontitis

Pivotal role in pathogenesis of periodontitis

Costantini 2020 [61]

Cross- sectional (Saliva Samples)

An increase in IL-35 salivary level was observed in periodontopathic patients with respect to the healthy controls

Pivotal role in pathogenesis of periodontitis

Hetta 2020 [34]

Cross- sectional (Serum Samples)

Serum levels of IL-35 were significantly higher in patients with periodontitis compared to the healthy controls

Pivotal role in pathogenesis of periodontitis

Jin 2017 [27]

Cross-sectional (GCF, Serum, periodontal tissues Samples)

IL-35 protein and periodontal clinical indicators were negatively correlated. It was hypothesized that the increased level of IL-35 plays a protective role in periodontal disease by maintaining immune system homeostasis and dampening the inflammatory response, and highlights IL-35 as a potential new therapy for the treatment of periodontitis

Anti-inflammatory activity

Jing 2019 [28]

Cross-sectional (gingival biopsies)

This study identified a subset of plasma cell which produces IL-35 and IL-37. This may regulate periodontitis pathogenesis by inhibiting alveolar bone loss through directly blocking osteoclast formation

Anti-inflammatory activity

Kalburgi 2013 [26]

Cross-sectional (gingival biopsies)

The increased expression of IL-35 in chronic and aggressive periodontitis suggests its possible role in pathogenesis of periodontitis

Pivotal role in pathogenesis of periodontitis

Köseoğlu 2015 [24]

Cross-sectional (GCF, Serum and Plasma samples)

IL-35 could have an important role to suppress the periodontal inflammation and maintain periodontal health

Anti-inflammatory activity

Maboudi 2019 [44]

Cross- sectional (GCF and Serum samples)

neither Type 2 diabetes mellitus nor chronic periodontitis differentially affects serum levels of IL-35

No significant association

Mitani 2015 [25]

Cross-sectional (GCF samples and gingival biopsies)

IL-35 level was significantly higher in GCF and gingival tissues of patients with periodontitis than healthy participants

Pivotal role in pathogenesis of periodontitis

Okada 2017 [62]

Cross-sectional (Peripheral blood mononuclear cells)

IL-35 could directly suppress IL-17 expression via RORα and RORγ t inhibition to restrain the excessive immune response in inflammatory conditions such as periodontitis

Anti-inflammatory activity

Raj 2018 [47]

Clinical trial (nonsurgical periodontal treatment)

(GCF and Serum Samples)

GCF and serum IL‑35 concentration among Chronic periodontitis individuals was highest among all the groups. Individuals receiving NSPT showed a significant reduction in IL‑35 levels as compared to CP individuals

Pivotal role in pathogenesis of periodontitis

Üstün 2018 [48]

Clinical trial (GCF samples)

The level of IL-35 significantly reduced after SRP in chronic periodontitis patients

Pivotal role in pathogenesis of periodontitis