Inflammatory Bone Loss in Experimental Periodontitis Induced by Aggregatibacter actinomycetemcomitans in Interleukin-1 Receptor Antagonist Knockout Mice

Abstract

cThe interleukin-1 receptor antagonist (IL-1Ra) binds to IL-1 receptors and inhibits IL-1 activity. However, it is not clear whether IL-1Ra plays a protective role in periodontal disease. This study was undertaken to compare experimental periodontitis induced by Aggregatibacter actinomycetemcomitans in IL-1Ra knockout (KO) mice and wild-type (WT) mice. Computed tomography (CT) analysis and hematoxylin-and-eosin (H&E) and tartrate-resistant acid phosphatase (TRAP) staining were performed. In addition, osteoblasts were isolated; the mRNA expression of relevant genes was assessed by real-time quantitative PCR (qPCR); and calcification was detected by Alizarin Red staining. Infected IL-1Ra KO mice exhibited elevated (P, <0.05) levels of antibody against A. actinomycetemcomitans, bone loss in furcation areas, and alveolar fenestrations. Moreover, protein for tumor necrosis factor alpha (TNF-␣) and IL-6, mRNA for macrophage colony-stimulating factor (M-CSF), and receptor activator of NF-B ligand (RANKL) in IL-1Ra KO mouse osteoblasts stimulated with A. actinomycetemcomitans were increased (P, <0.05) compared to in WT mice. Alkaline phosphatase (ALP), bone sialoprotein (BSP), osteocalcin (OCN)/bone gla protein (BGP), and runt-related gene 2 (Runx2) mRNA levels were decreased (P, <0.05). IL-1␣ mRNA expression was increased, and calcification was not observed, in IL-1 Ra KO mouse osteoblasts. In brief, IL-1Ra deficiency promoted the expression of inflammatory cytokines beyond IL-1 and altered the expression of genes involved in bone resorption in A. actinomycetemcomitans-infected osteoblasts. Alterations consistent with rapid bone loss in infected IL-Ra KO mice were also observed for genes expressed in bone formation and calcification. In short, these data suggest that IL-1Ra may serve as a potential therapeutic drug for periodontal disease.

Polymorphism IL-1RN rs419598 reduces the susceptibility to generalized periodontitis in a population of European descent

“…Thus, a study of IL-1ra knockout mice showed a greater antigenic response to A . actinomycetemcomitans infection, with an increased production of pro-inflammatory cytokines, rapid loss of alveolar bone (assessed by micro-CT), lesser formation of mineralized matrix, and greater tissue expression of bone resorption markers[33]. Our results are compatible with the conclusion of Yucesoy et al that an imbalance of the IL-1β/IL-1ra ratio in periodontal tissue appears to reduce susceptibility to periodontitis [34].…”

NLRP3 inflammasome is required for apoptosis of Aggregatibacter actinomycetemcomitans-infected human osteoblastic MG63 cells

“…In line with prior studies, the secretion of IL-1␤ and IL-18 was extensively enhanced when MG63 cell cultures were challenged with the bacteria (Kelk et al, 2011;Belibasakis and Johansson, 2012). The excessive pro-inflammatory response triggered by A. actinomycetemcomitans contributes significantly to alveolar bone loss in periodontitis (Izawa et al, 2014).…”

The interleukin (IL)-1 cytokine family – Balance between agonists and antagonists in inflammatory diseases

“…Mice lacking IL-1Ra in all tissues or only cell type-specifically Increased severity of IMQ-induced skin inflammation [176] in myeloid cells are more susceptible to lethal endotoxemia [157,158] as well as to inflammatory bone loss in bacterial peridontitis [159]. In contrast, mice lacking IL-1Ra have an improved survival upon infection with Listeria monocytogenes [157].…”