IL-33 and IL-17 family cytokines (IL-17A – IL-17F) have been shown to play roles in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. However knowledge of their role in periodontal disease pathogenesis is limited. The aim of this study was therefore to determine clinical associations between IL-33 and IL-17 family cytokines and chronic periodontitis. In addition, to begin to investigate the biological significance of these associations using in vitro model systems.97 patients with chronic periodontitis and 77 healthy volunteers were recruited in Glasgow and Newcastle. Serum, gingival crevicular fluid (GCF) and saliva were analysed for levels of IL-33 and IL-17 family cytokines by ELISA. Periodontal tissues from 17 chronic periodontitis patients and 10 healthy subjects from Glasgow were also investigated for IL-33 and IL-17 family cytokines mRNA expression by real time PCR. Immunohistochemical analysis was also performed on tissue to investigate expression of IL-33 and IL-17E at the protein level. In vitro experiments were performed using the OKF6/TERT-2 oral keratinocyte cell line and primary human gingival epithelial (PHGE) cells. The cells were stimulated with either a live Porphyromonas gingivalis monospecies biofilm or recombinant cytokines and changes in expression of cytokines, chemokines and their receptors evaluated by real-time PCR, immunocytochemical analysis or ELISA. In addition, transcriptional activity was monitored by analysis of changes in the phosphorylation (activation) of the NF-κB p65 subunit transcription factor using serum, GCF and saliva. IL-17A and IL-17A/F levels were higher in chronic periodontitis patients, but serum IL-17E was lower.IL-17A, IL-17A/F and the serum IL-17A:IL-17E ratio correlated positively with clinical parameters. IL-33, and IL-17 family cytokine (except IL-17B) gene transcripts were higher in tissue of chronic periodontitis patients. In addition, IL-33, ST2, IL-17E and IL-17RB proteins are expressed in periodontal tissues. Furthermore, IL-33 protein expression is upregulated in tissue of chronic periodontitis patients. In vitro models showed that IL-33 and its receptors (ST2 and ST2L) are expressed by oral keratinocytes (OKF6/TERT-2 cells and PHGE cells) and IL-33 expression up-regulated in response to P. gingivalis. However, IL-33 failed to induce expression of a range of inflammatory mediators and receptors in OKF6/TERT-2 cells.In vitro, IL-17E inhibited P. gingivalis monospecies biofilm and IL-17A induced expression of chemokines (IL-8 and/or CXCL5) by OKF6/TERT-2 cells at the transcriptional level by blocking the phosphorylation (activation) of the NF-κB p65 subunit.This study demonstrates clinical associations between IL-33 and IL-17 family cytokines and chronic periodontitis. The expression of IL-33 by oral keratinocytes and its up regulation upon exposure to P. gingivalis suggest it plays a role in the innate immune response to pathogens within the periodontium. However, the role of IL-33 in the periodontal inflammatory response remains to be elucidated. The negative correlations between serum levels of IL-17A and IL-17E and correlations with disease parameters, combined with their differing effects on the induction of expression of key neutrophil chemoattractants (CXCL5 and CXCL8), suggest opposing roles in periodontal immunity. Indeed, it can be hypothesised that the differential regulation of chemokine expression is due to IL-17A having pro- and IL-17E having anti-inflammatory properties. Indeed, as neutrophils play a key role in the early events associated with periodontal disease progression, the data suggests IL-17E is a rational target for therapeutic intervention.
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The role of IL-33 and IL-17 family cytokines in periodontal disease
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