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

Abstract

IL-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.