Cytokines in gingivitis and periodontitis: from pathogenesis to therapeutic targets

Abstract

Chronic inflammatory processes in the oral mucosa and periodontitis are common disorders caused by microflora and microbial biofilms. These factors activate both the innate and adaptive immune systems, leading to the production of pro-inflammatory cytokines. Cytokines are known to play a crucial role in the pathogenesis of gingivitis and periodontitis and have been proposed as biomarkers for diagnosis and follow-up of these diseases. They can activate immune and stromal cells, leading to local inflammation and tissue damage. This damage can include destruction of the periodontal ligaments, gingiva, and alveolar bone. Studies have reported increased local levels of pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta), tumor necrosis factor (TNF), IL-6, IL-17, and IL-23, in patients with periodontitis. In experimental models of periodontitis, TNF and the IL-23/IL-17 axis play a pivotal role in disease pathogenesis. Inactivation of these pro-inflammatory pathways through neutralizing antibodies, genetic engineering or IL-10 function has been demonstrated to reduce disease activity. This review discusses the role of cytokines in gingivitis and periodontitis, with particular emphasis on their role in mediating inflammation and tissue destruction. It also explores new therapeutic interventions that offer potential for research and clinical therapy in these chronic inflammatory diseases.

Keywords: cytokine targeting; cytokines; oral mucosa; pathogenesis; periodontitis.

Figure 1

The role of cytokines in the pathogenesis of periodontitis is a topic of significant interest in the field of periodontal research. Genetic and environmental factors have been identified as predisposing factors for the development of periodontitis, which is a chronic inflammatory process involving the activation of both innate and adaptive immune cells. The microbiota-driven activation of innate immune cells leads to the production of pro-inflammatory cytokines such as IL-1, IL-6, TNF, and IL-23. IL-1, IL-6 and TNF are produced by antigen presenting cells such as macrophages, and promote inflammation by inducing chemotaxis and activation of neutrophils and by activating T cells and fibroblasts. IL-23 is produced by antigen-presenting cells and gingival epithelial cells. IL-1 and IL-23 induce the activation of Th17 cells, which can produce IL-17A/F, IFN-gamma, IL-21 and IL-6. Th17 cells induce the activation of RANKL expression by osteoblasts and fibroblasts, thereby inducing osteoclastogenesis and bone loss in periodontitis. Figure was created with BioRender.

Figure 2

Potential therapeutic avenues for periodontitis based on modulation of cytokine function have been identified. In experimental models of periodontitis, several strategies modulating cytokine function have been shown to suppress inflammation and bone loss. Administration of IL-17 antibodies led to suppression of inflammatory activity in experimental periodontitis. Moreover, IL-1RA and IL-6R blockade (via tocilizumab) have been shown to block Th17 cell activity and local inflammation. Furthermore, IL-10 has been identified as an important suppressor of Th17 activity, suggesting that strategies for inducing IL-10 expression or function might be used for periodontitis therapy. Finally, studies in experimental periodontitis and patients with periodontitis have suggested that administration of TNF blockers such as etanercept, adalimumab, and infliximab might be used to suppress inflammation in periodontitis. Figure was created with BioRender.