IL-1 Superfamily Members and Periodontal Diseases

Abstract

Periodontitis is a complex, multifactorial chronic disease involving continuous interactions among bacteria, host immune/inflammatory responses, and modifying genetic and environmental factors. More than any other cytokine family, the interleukin (IL)-1 family includes key signaling molecules that trigger and perpetuate periodontal inflammation. Over the years, the IL-1 family expanded to include 11 members of cytokines, some with agonist activity (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ), receptor antagonists (IL-1Ra, IL-36Ra), and 2 anti-inflammatory cytokines (IL-37, IL-38). The IL-1 receptor antagonist (IL-1Ra) has emerged as a pivotal player in the defense against periodontitis. IL-33 primarily induces the production of Th2-associated cytokines but acts as an "alarmin" via stimulation of mast cells. The IL-36 subclass of cytokines may be important in regulating mucosal inflammation and homeostasis. IL-37 suppresses innate and acquired immune responses. IL-38 is the most recent member of the IL-1 superfamily and has anti-inflammatory properties similar to those of IL-37 but through different receptors. However, limited evidence exists regarding the role of IL-37 and IL-38 in periodontitis. Despite the development of IL-1 blocking agents, therapeutic blockade of select IL-1 family members for periodontitis has only been partially investigated in preclinical and clinical research, while the development of IL-37 and IL-38 as novel anti-inflammatory drugs has not been considered adequately. Here, we review the key properties of the IL-1 family members and provide insights into targeting or promoting select cytokines as new therapeutic agents.

Keywords: IL-18; IL-33; cytokines; inflammation; interleukin 1; periodontitis.

Figure.

Diagrammatic representation of the key immune cells and interleukin (IL)–1 family members involved in periodontal inflammation and alveolar bone loss. The development of a dysbiotic dental biofilm triggers the release of IL-1 proinflammatory cytokines (e.g., IL-1α, IL-1β, IL-18, IL-36) from oral junctional epithelial cells (1). Proinflammatory signals combined with translocated bacteria or bacterial products (e.g., LPS) in periodontal tissues activate both innate (PMNs, mast cells, macrophages, dendritic cells) and adaptive (T cells, B cells) immune cells to release inflammatory mediators (2). IL-1 proinflammatory cytokines stimulate vasodilation and increase vascular permeability, amplifying the recruitment of inflammatory cells in the periodontium (chemotaxis) (3). Macrophages are the main sources of IL-1 proinflammatory cytokines that magnify periodontal inflammation. Macrophages and PMNs also release MMPs that result in the degradation of extracellular matrix (4). IL-33 released from oral epithelial cells activates mast cells that secrete further IL-33, triggering osteoclastogenesis and alveolar bone loss via increased RANKL (5). IL-18 is mainly released from DCs that can trigger differentiation of Th1 and Th17 cells and upregulate the release of IL-17, TNF-α, and IL-1β, promoting more periodontal tissue destruction (6). Increased levels of IL-1 proinflammatory cytokines (IL-1β, IL-33, and IL-36) are positively correlated with increased RANKL release; both stimulate recruitment of osteoclast progenitors and formation of osteoclast precursors (7) that turn into activated osteoclasts, responsible for alveolar bone resorption that occurs in periodontitis (8). IL-1 family members with anti-inflammatory properties (IL-1Ra, IL-36Ra, IL-37, and IL-38) aim to restrain the magnitude of periodontal inflammation stimulated by IL-1 proinflammatory cytokines. DC, dendritic cell; LPS, lipopolysaccharide, MMPs, matrix metalloproteinases; PMN, polymorphonuclear neutrophil; RANKL, receptor activator of nuclear factor kappa-β ligand. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.