The role of IL-18 in cross-susceptibility between periodontal disease and diabetes

PhD ThesisIL-18 is a cytokine with a number of important actions central to innate and adaptive immune responses. There is some evidence that IL-18 is elevated in gingival crevicular fluid (GCF) and associated with the severity of periodontal disease. In addition, the pro-inflammatory adipokine leptin is elevated in type 2 diabetes mellitus (T2DM) and obesity. The action of leptin may be one factor which underpins the cross-susceptibility between these disorders and chronic inflammatory diseases such as periodontal disease. However, the relationship between IL-18 and leptin in periodontal diseases still remains to be determined. Therefore, the objective of this study was to determine the serum concentrations of IL-18 in periodontal disease subjects with and without T2DM. In addition, the present study aimed to investigate how IL-18 is regulated by leptin in human monocytes, as well as the extent to which caspase-1 plays a role in this pathway. The present study demonstrated for the first time that serum IL-18 levels were significantly elevated in T2DM patients with periodontitis compared to periodontally healthy individuals. The levels of serum IL-18 are positively correlated with HbA1c and BMI but not with hsCRP levels. In vitro, leptin was found to significantly increase IL-18 secretion by THP-1 and primary human monocytes but had no effect on IL-18 mRNA expression. Activation of JAK-2 tyrosine kinase is a primary event in leptin receptor (ObRb) signalling and co-incubation of monocytes with the JAK-2 inhibitor AG490 significantly reduced leptin-induced IL-18 release. Interestingly, addition of exogenous ATP (a known inflammasome-activating signal) significantly enhanced IL-18 release in leptin-stimulated monocytes. These data suggest that leptin stimulates IL-18 via JAK-2 signalling and this is the result of activation of IL-18 processing rather than IL-18 transcription. The present study provided further evidence to support this hypothesis: leptin up-regulated caspase-1 activity as demonstrated by chromogenic peptide assays, Western blot analysis revealed that leptin modulated the levels of active caspase-1 p20 and the effect of leptin on IL-18 release was inhibited by a caspase-1 inhibitor (Ac-YVAD-cmk). Leptin alone was also found to stimulate endogenous ATP release from monocytes which suggests one possible mechanism for inflammasome activation by this adipokine. In conclusion, the present study demonstrates a novel role for leptin in immune responses by monocytes. The up-regulation of serum IL-18 levels may be directly relevant to periodontal destruction in diabetic individuals. Leptin enhances IL-18 secretion via modulation of the caspase-1 inflammasome function and this process may contribute to the cross-susceptibility between T2DM and periodontal diseases.Anandhamahidol foundation

Leptin induces the generation of procoagulant, tissue factor bearing microparticles by human peripheral blood mononuclear cells

Obesity is linked to increased thrombotic risk. Circulating leptin concentration correlates with body mass index. Microparticles are small (.05-1μm) vesicles shed by activated and apoptotic cells, involved in numerous pathophysiologically relevant phenomena including blood coagulation and thrombosis. We tested the hypothesis that leptin induces the shedding of procoagulant, tissue factor bearing microparticles by human peripheral blood mononuclear cells, and investigated the intracellular mechanisms leading to microparticle release upon incubation with leptin

Anti-Early Stage of Bacterial Recolonization Effect of Curcuma longa Extract as Photodynamic Adjunctive Treatment

Objective. To evaluate the amount of Fusobacterium nucleatum (F. nucleatum) and Prevotella intermedia (P. intermedia) on subgingival recolonized plaque after mechanical debridement and photodynamic treatment by using blue light-emitting diodes (LEDs) in combination with topical Curcuma longa gel extract. Methods. A total of 12 subjects with stage III grade B periodontitis were recruited for the study. Maxillary posterior teeth with periodontal pocket >4 mm were selected. These teeth were examined for periodontal clinical data at baseline and at 1, 2, 4, and 6 weeks after treatment. All remaining teeth were treated by scaling and root planing (SRP). Then, the teeth were bilaterally divided using randomized split-mouth design with and without photodynamic adjunctive therapy (PDT). Samples of the subgingival microbiota were obtained in each visit. All samples were analyzed by multicolor TaqMan real-time polymerase chain reaction (PCR) for the presence of target bacteria. Results. Throughout the six-week follow-up, long-term improvement of probing depth and bleeding on probing was revealed on the PDT group. The number of subgingival F. nucleatum and P. intermedia also significantly reduced, compared to the baseline. There was a statistically significant recolonization in F. nucleatum and P. intermedia number after 2 and 4 weeks of conventional SRP, respectively. Our quantitative PCR method showed no significant recolonization of those subgingival bacteria on PDT sites throughout the 6-week study duration. Conclusion. The results showed that adjunctive photodynamic treatment by using blue LEDs in combination with topical Curcuma longa gel extract was effective to alter the recolonization patterns of F. nucleatum and P. intermedia after conventional debridement

Collagen-Based Biomaterials in Periodontal Regeneration: Current Applications and Future Perspectives of Plant-Based Collagen

Collagen is the most widely distributed protein in human body. Within the field of tissue engineering and regenerative medical applications, collagen-based biomaterials have been extensively growing over the past decades. The focus of this review is mainly on periodontal regeneration. Currently, multiple innovations of collagen-based biomaterials have evolved, from hemostatic collagen sponges to bone/tissue regenerative scaffolds and injectable collagen matrices for gene or cell regenerative therapy. Collagen sources also differ from animal to marine and plant-extracted recombinant human type I collagen (rhCOL1). Animal-derived collagen has a number of substantiated concerns such as pathogenic contamination and transmission and immunogenicity, and rhCOL1 is a potential solution to those aforementioned issues. This review presents a brief overview of periodontal regeneration. Also, current applications of collagen-based biomaterials and their mechanisms for periodontal regeneration are provided. Finally, special attention is paid to mechanical, chemical, and biological properties of rhCOL1 in pre-clinical and clinical studies, and its future perspectives in periodontal regeneration are discussed

The Prevalence of Xerostomia in Older Thai Individuals with Type II Diabetes Mellitus and Its Association with Type of Toothpaste and Oral Functions: A Cross-Sectional Study Using Questionnaires

Aim: To investigate the prevalence of xerostomia in older people with diabetes mellitus and its impacts on oral functions, as well as to determine potential risk factors for xerostomia. Methods: An analytical cross-sectional study was conducted on 623 older type 2 diabetes mellitus (T2DM) Thai people using valid structural questionnaires. Patients were interviewed, and data were recorded. Xerostomia was assessed using subjective symptom questionnaires. Risk factors for xerostomia were analyzed using bivariate and multiple logistic regression analyses. Results: Among the study participants, 38.4% of the older T2DM people had xerostomia, which is associated with sex, age, type of toothpaste, years of diabetes, hemoglobin A1c level, other systemic diseases, medication, smoking, alcohol consumption, and denture wearing. It was significant that xerostomia was associated with toothpaste containing spicy herbal extracts (OR: 9.32 [3.46 to 15.25]), while toothpaste containing artificial sweeteners tended to lower the risk of xerostomia. In addition, older T2DM adults with xerostomia had greater impaired oral functions, which include difficulties in speaking (OR: 3.31 [1.11 to 9.80]), tasting (OR: 5.12 [3.26 to 8.06]), swallowing (OR: 3.59 [2.32 to 5.53]), and chewing (OR: 3.34 [1.15 to 5.82]). Conclusions: Xerostomia is prevalent in older Thai people with T2DM. The results suggest that toothpaste containing spicy herbal extracts might increase the risk of xerostomia, resulting in various oral function problems. Therefore, greater awareness of xerostomia in this group should be raised to monitor dental health, and professionals should work in parallel with other aspects of oral health promotion

Leptin enhances the secretion of interleukin (IL)-18, but not IL-1β, from human monocytes via activation of caspase-1

Circulating levels of leptin are elevated in type-2 diabetes mellitus (T2DM) and leptin plays a role in immune responses. Elevated circulating IL-18 levels are associated with clinical complications of T2DM. IL-18 regulates cytokine secretion and the function of a number of immune cells including T-cells, neutrophils and macrophages and as such has a key role in immunity and inflammation. Pro-inflammatory monocytes exhibiting elevated cytokine secretion are closely associated with inflammation in T2DM, however, little is known about the role of leptin in modifying monocyte IL-18 secretion. We therefore aimed to investigate the effect of leptin on IL-18 secretion by monocytes. We report herein that leptin increases IL-18 secretion in THP-1 and primary human monocytes but has no effect on IL-18 mRNA. Leptin and LPS signalling in monocytes occurs by overlapping but distinct pathways. Thus, in contrast to a strong stimulation by LPS, leptin has no effect on IL-1β mRNA levels or IL-1β secretion. In addition, LPS stimulates the secretion of IL-6 but leptin did not whereas both treatments up regulate IL-8 secretion from the same cells. Although leptin (and LPS) has a synergistic effect with exogenous ATP on IL-18 secretion in both THP-1 and primary monocytes, experiments involving ATP assays and pharmacological inhibition of ATP signalling failed to provide any evidence that endogenous ATP secreted by leptin-stimulated monocytes was responsible for enhancement of monocyte IL-18 secretion by leptin. Analysis of the action of caspase-1 revealed that leptin up regulates caspase-1 activity and the effect of leptin on IL-18 release is prevented by caspase-1 inhibitor (Ac-YVAD-cmk). These data suggest that leptin activates IL-18 processing rather than IL-18 transcription. In conclusion, leptin enhances IL-18 secretion via modulation of the caspase-1 inflammasome function and acts synergistically with ATP in this regard. This process may contribute to aberrant immune responses in T2DM and other conditions of hyperleptinemia

Do patients with aggressive periodontitis have evidence of diabetes? A pilot study

BACKGROUND AND OBJECTIVE: Complex relationships exist between diabetes and periodontal disease. Diabetes is accepted as a risk factor for periodontal disease, and recent evidence supports the existence of a bidirectional relationship between these two diseases. It has been hypothesized that inflammation, lipids and adipokines may mediate these relationships. However, research regarding the above relationships with respect to aggressive periodontitis is very limited. This pilot study aimed to investigate whether patients with aggressive periodontitis (not previously diagnosed with diabetes) have evidence of diabetes and have altered serum levels of inflammatory mediators, lipids and adipokines. MATERIAL AND METHODS: Glycaemic control markers (random plasma glucose and glycated haemoglobin), inflammatory mediators (high-sensitivity C-reactive protein, tumour necrosis factor-α, interleukin-1β, interleukin-6, interferon-γ and interleukin-18), lipids (triglycerides, total cholesterol and high-density lipoprotein-cholesterol) and adipokines (leptin, adiponectin and resistin) were measured in serum samples from 30 patients with aggressive periodontitis and 30 age- and sex-matched periodontally healthy control subjects, none of whom had a previous diagnosis of diabetes. RESULTS: Levels of glycaemic control markers, inflammatory mediators, lipids and adipokines were not significantly different (p > 0.05) between the aggressive periodontitis patients and healthy subjects for unadjusted and adjusted analyses (adjusting for body mass index, smoking, ethnicity, age and sex). The p-value for the adjusted analysis of adiponectin in female aggressive periodontitis patients compared with the female control subjects reached 0.064, the mean adiponectin level being lower in the female aggressive periodontitis patients (4.94 vs. 5.97 μg/mL). CONCLUSION: This pilot study provided no evidence to suggest that patients with aggressive periodontitis (not previously diagnosed with diabetes) have evidence of diabetes or altered serum levels of inflammatory mediators, lipids and adipokines

Anti-inflammatory activity of soluble chito-oligosaccharides (CHOS) on VitD3-induced human THP-1 monocytes.

Chito-oligosaccharides (CHOS) are oligomers of D-glucosamine and N-acetyl-glucosamine. Anti-inflammatory activities of a wide variety of CHOS mixtures have previously been reported, mainly based on studies with mouse models and murine macrophages. Since the mouse and human immune systems are quite different, gaining insight into the activity of CHOS on human cell lines, using well-characterized CHOS mixtures, is of considerable interest. Bacillus subtilis chitosanase (BsCsn46A) can efficiently convert chitosan to mixtures of water soluble low molecular weight CHOS. Here, the anti-inflammatory activity of a properly characterized CHOS mixture was studied, using human THP-1 cells that were differentiated to mature monocytes using vitamin D3. Addition of CHOS reduced the production of multiple pro-inflammatory cytokines associated with bacterial lipopolyssacharide (LPS)-stimulated inflammation, in a dose-dependent manner and without affecting cell viability. Interestingly, only minimal effects of CHOS were observed in similar experiments with phorbol 12-myristate 13-acetate- (PMA-) differentiated, macrophage-like, THP-1 cells. Altogether, in addition to showing promising biological effects of well-characterized low molecular weight soluble CHOS in a human system, the present study also points at Vitamin D3-stimulated THP-1 cells as a favorable system for assessing the anti-inflammatory activity of bioactive compounds