Table 1.
General characteristics and functions of pro-inflammatory and anti-inflammatory cytokines which occur within the periapical lesions on the basis of the literature [28,29,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50].
| Cytokine (Abbreviation) |
Cytokine Receptors |
Cytokine-Secreting Cells |
Target Cells |
Functions | Bone Effect |
|---|---|---|---|---|---|
| Interleukin-1 alpha (IL-1α) |
Interleukin-1 receptor (IL-1R): type I (IL1R1) and type II (ILL1R2) |
monocytes, macrophages, polymorphonuclear leucocytes (PMNs), fibroblasts, osteoclasts, epithelial cells, endothelial cells, B cells | T-cells, B-cells, neutrophils, osteoblasts, tissue cells |
Induces the inflammation and regulates immune system by chemotactically activation of PMN. Stimulates the production of PG, proteolytic enzymes and proinflammatory cytokines IL-6, IL-8. | Bone destruction: stimulates bone resorption and inhibits bone formation. Inhibits osteoblasts differentiation and probably induces apoptosis of osteoblasts. |
| Interleukin-1 beta (IL-1β) |
Interleukin-1 receptor (IL-1R): type I (IL1R1) and type II (ILL1R2) |
macrophages, dendritic cells, osteoblasts, fibroblasts (i.e., gingival fibroblasts, periodontal ligament cells), osteoblasts, epithelial and endothelial cells | T-cells, fibroblasts, epithelial cells, endothelial cells |
Induces the inflammation: accelerates blood flow in inflamed tissue, supports leucocyte recruitment and neutrophil diffusion and accumulation. |
Bone destruction: promotes bone resorption by stimulating production of MMPs, (mainly MMP-9), RANKL, IL-6. |
| Interleukin-18 (IL-18) |
Interleukin-18 receptor (IL-18R, CD218a) |
macrophages, dendritic cells, monocytes, keratinocytes, CNS cells, osteoblasts, endothelial cells |
T-cells (CD4 and CD8), NK-cells, basophils, mast cells |
Induces the production of IFNγ by T-cells and NK-cells. Induces Th cell-mediated immunity. Promotes proliferation of Th1. | Bone destruction: promotes osteoclastogenesis by regulation of RANKL production. |
| Interleukin-6 (IL-6) |
Interleukin-6 receptor (IL-6R, CD126) |
monocytes, polymorphonuclear leucocytes (PMNs), osteoclasts, macrophages, T-cells (Th2), B-cells, fibroblasts, endothelial cells | T-cells, B-cells, neutrophils, osteoblasts, tissue cells |
Acute phase of inflammation: activates PMNs and T-cells. Stimulates B-lymphocytes differentiation into plasma cell. Induces protein synthesis. Suppresses the production of IL-1. |
Bone destruction: induces bone resorption by promoting osteoclast differentiation. |
| Interleukin-8 (IL-8) |
Interleukin-8 receptor A (IL-8RA, CXCR1) and interleukin-8 receptor B (IL-8RB, CXCR2) |
monocytes, macrophages, PMNs, bone marrow stromal cells, osteoblasts, osteoclasts, synovial fibroblasts, chondrocytes | neutrophils, basophils |
Chemotactic factor: attracts and activates PMNs and osteoclasts. |
Bone destruction (potentially): stimulates osteoclastogenesis by osteoclasts differentiation and production, by stimulating RANKL expression and directly by stimulation of osteoclasts pro-duction and activation. |
| Interleukin-10 (IL-10) |
Interleukin-10 receptor: (IL-10R) type I (IL-10R1) and type II (IL-10R2) |
T-cells, monocytes, dendritic cells, B-cells, mast-cells, eosinophils | Th1, macrophages, NK-cells |
Inhibits the production of cytokines by Th1: IL-1, IL-6 and IFNγ. Inhibits synthesis of NO and proteases (such as collagenases). Stimulates the secretion of tissue inhibitors of metalloproteinases and osteoprotegerin. | Inhibits bone resorption, suppresses the osteoclastogenesis and activates proliferation of osteoblasts. |
| Interleukin-17 | Interleukin-17 receptor (IL-17R) | Th17, Tregs | T-cells, B-cells, osteoblasts, tissue cells | Induces the inflammation. Activates secretion of IL-1, IL-6, TNFα, GCP-2 and IL-8. Induces migration of neutrophils. |
Bone destruction: stimulates bone resorption, stimulates the production of RANKL by osteoblast and mesenchymal stem cells, disturbs balance of RANKL/OPG, which promotes osteoclastogenesis. |
| Tumor Necrosis Factor α (TNFα) |
Tumor necrosis factor receptor 1 (TNFR1, CD120a); Tumor necrosis factor receptor 2 (TNFR2, CD120b) |
macrophages, monocytes, lymphocytes (Th1), mast cells | macrophages, granulocytes, endothelial cells | Induces the inflammation by activating lymphocytes and monocytes. | Bone destruction: stimulates bone resorption, supports osteoclastogenesis with RANKL, promotes differentiation of osteoclasts and suppresses formation of osteoblasts. |
| Interferon gamma (IFNγ) |
Interferon gamma receptor 1 (IFNGR1, CD119) and Interferon gamma receptor 2 (IFNGR2) |
T-cells (CD4+, CD8+), Treg cells, B-cells, NK cells | monocytes, lymphocytes, tissue cells, mesenchymal stem cells (MSCs) | Activation of macrophages and differentiation of B-cells. Induces production of IL-1, NO and oxygen. | Inhibits bone resorption: inhibits production and differentiation of osteoclasts, activates apoptosis of osteoclasts. Indirectly down-regulates RANKL-depended osteoclastogenesis. Promotes differentiation of osteoblast from MSCs. |
| Interleukin-4 (IL-4) |
Interleukin-4 receptor (IL-4, CD124) | Th2 | Th17 | Suppresses Th17 formation and production of IL-1. Stimulates the secretion of tissue inhibitors of metalloproteinases and osteoprotegerin. | Inhibits bone resorption, inhibits the osteoclast differentiation. It may promote osteoprotegerin pro-duction. |
| Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF aka CSF2) |
GM-CSF receptor (GM-CSFR) | macrophages, mast cells, T-cells, fibroblasts, NK cells, endothelial cells | bone marrow stem cells, macrophages, neutrophils | Takes part in hematopoiesis. Induces production of granulocytes (neutrophils, basophils, eosinophils) and monocytes from bone marrow stem cells. Activates macrophages. Enhances neutrophils migration. | Inhibits formation of osteoclasts from progenitor cells, reduces the RANKL/RANK activity. The increased level of dendritic cells makes GM-CSF activate osteoclastogenesis. |
B-cell–lymphocyte type B, CD–cluster of differentiation, CNS cells–central nervous system cells, GCP-2–granulocyte chemotactic protein–2, IFNγ–interferon γ, IL–interleukin, MMP–matrix metalloproteinase, MSC–mesenchymal stem cell, NK–natural killer T-cell, NO–nitrous oxide, OPG–osteoprotegerin, PG–prostaglandin, PMN–polymorphonuclear leucocytes, RANK–Receptor Activator for Nuclear Factor κ B, RANKL–Receptor Activator for Nuclear Factor κ B Ligand, T-cell–lymphocyte type T, Th–T helper lymphocyte, TNFα–tumor necrosis factor α, Treg cell–regulatory T cell.