Effects of cytokines on prostaglandin E and cAMP levels in human periodontal ligament fibroblasts in vitro

doi:10.1016/0003-9969(90)90186-E

Archives of Oral Biology

Volume 35, Issue 5, 1990, Pages 387-395

https://doi.org/10.1016/0003-9969(90)90186-E Get rights and content

Abstract

The stimulation of PGE synthesis and cAMP production by cytokines have important physiological effects in many target tissues. The effects of interleukin-1α and -1β, tumour necrosis factor-α and interferon-γ on PGE and cAMP production by periodontal ligament fibroblasts were studied. Fibroblasts in the 4th–6th passage, grown and maintained in DMEM supplemented with 10% equine serum, were incubated with graded doses of the various cytokines for 0.25, 0.5, 1, 2, 4, 24, 48 or 72 h. At the end of each incubation, PGE in the medium and the cellular content of cAMP were evaluated by a combined immunohistochemical microphotometric procedure, and conventional radiometric assays. The fibroblasts responded to all the cytokines with a dose- and time-related increase in the levels of PGE and cAMP. Such increases were inhibited by the inclusion of indomethacin in the medium. The addition of exogenous PGE reversed that inhibition in respect of cAMP production. Immunohistochemical localization showed PGE predominantly in the cytoplasm and cAMP in the nucleus. These findings indicate that: (1) human periodontal ligament fibroblasts respond to these cytokines by increased synthesis of PGE and the production of cAMP; and (2) the cAMP production is secondary to the PGE synthesis. They suggest that these cytokines may regulate the function of these fibroblasts in physiological remodelling of the periodontium, as well as in inflammatory reactions.

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The best way to overcome this problem is to speed up tooth movement from its usual rate of 0.8 mm to 1.2 mm per month [1], and thus the mechanics to accelerate the pace of tooth movement has received more attention recently. The finding that cells can respond biologically to two or more signals, physical, chemical, or surgical, which when applied simultaneously, has created an insight that accelerated tooth movement can become a clinical reality [2], leading to experiments and clinical trials. The efforts to move teeth with a combined orthodontic and surgical approach were described by Kole [3,4], who identified the main layer to resist tooth movement is cortical bone, and corticotomies aid in faster tooth movement.
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Twenty patients (10 boys and 10 girls) with a mean age of 14.5 years and requiring first premolar extractions for orthodontic treatment were included. This split mouth study was carried out where maxillary canine retraction was done by active tie-backs, with corticotomy on the experimental side and without corticotomy on the control side. Rate of retraction was assessed with digital Vernier calipers. Gingival crevicular fluid samples were collected before starting treatment and at 3 days, 7 days, and 1 month from the distal sides of the canine of both sides after the force was applied.
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It was concluded that alveolar corticotomy increased rate of canine retraction by approximately 40%, increased catabolic activities approximately 250%, and increased anabolic activities approximately 42%.
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IL-1β attracts leukocytes and stimulates endothelial cells, fibroblasts, osteoclasts, and osteoblasts to enhance bone resorption and inhibit bone formation.34 TNF-α couples with macrophage colony-stimulating factor to directly stimulate osteoclast differentiation.35,36 Monocyte chemoattractant/chemotactic protein-1 (MCP-1 or CCL2) plays an important role in promoting chemotaxis, differentiation, and activation of osteoclasts.37
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We studied 18 healthy subjects, adolescents (11-14 years) and adults (21-45 years), with Class II Division 1 malocclusion requiring 4 first premolar extractions. Canines were retracted with a constant force of 50 cN. Gingival crevicular fluid was collected before orthodontic treatment and at days 1, 7, 14, and 28 after the canine retraction. Cytokine (IL-1β, CCL2, TNF-α) and osteoclast markers (RANKL and MMP-9) were measured using antibody-based protein assays. Pain and discomfort were monitored with a numeric rating scale. The canine retraction rate was measured from study models taken at days 28 and 56.
Although the cytokine and osteoclast markers increased significantly in both age groups at days 1, 7, and 14, the increases were greater in adults than in adolescents. Interestingly, the rate of tooth movement in adults was significantly slower than in adolescents over the 56-day study period. Adults also reported significantly more discomfort and pain.
Age is a significant variable contributing to the biologic response to orthodontic tooth movement. Adults exhibited a significantly higher level of cytokine and osteoclasts activity but, counterintuitively, had a significantly slower rate of tooth movement.
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Moreover, the production level of IL-1 in gingival crevicular fluid is correlated with the severity of the disease [69]. Thus, higher concentration of IL-1 increases the production of cAMP, PGE2, collagenase and plasminogen activator; and PGE2 mediated with cAMP promotes bone resorption and stimulates MMP activity (Fig. 9) [18,70,71]. Mononuclear cell cultures were stimulated with LPS in the presence or absence of CH3SH, and the IL-1-dependent cellular proliferation was determined.
Volatile sulfur compounds (VSCs), mainly composed of hydrogen sulfide (H₂S) and methyl mercaptan (CH₃SH), cause halitosis. VSCs increase the permeability of a model for gingival crevicular epithelia, causing an increase in the penetration of lipopolysaccharide, as well as prostaglandin, into the tissue. VSCs inhibit the proliferation of human gingival fibroblasts (HGF), human gingival epithelial cells (HGEC) and osteoblasts. H₂S also causes apoptosis in HGF and HGEC. Furthermore, VSCs increase collagen degradation and reduce collagen synthesis in HGF and suppress wound healing, especially the formation of basal membrane and Type IV collagen synthesis. Moreover, VSCs stimulate interleukin-1 production, resulting in an increase in prostaglandin E and matrix metalloproteinase 1. Thus, VSCs may induce the initial damage to the epithelial barrier in the progression of periodontal disease. VSCs, especially H₂S, strongly inhibit cytochrome c oxidase, which is a key enzyme for oxidative phosphorylation in the respiratory chain. Therefore, high concentration of VSCs causes lethal toxicities as well as cyanide. On the other hand, very low concentration of H₂S at lower concentration in periodontal pocket causes genomic DNA damages in both HGF and HGEC. It has been suggested that VSCs may be one of the contributing factors for carcinogenesis because of increasing oxidative stress, and as the Ras/mitogen activated protein kinase signaling pathway, which is constitutively activated in many types of cancer, is enhanced.
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Recent studies8,31–33 have shown that TNFα directly stimulates the differentiation of osteoclast progenitors to osteoclasts in the presence of M-CSF. Davidovitch et al.8 and Saito et al.31 demonstrated marked increases in the staining intensity for IL-1 and TNFα in cells of periodontal ligament and alveolar bone during orthodontic tooth movement in cats. In light of these findings, our results suggest that osteoblasts produce various cytokines that promotes the osteoclast formation from mechanical stress and the production of cytokines was dependent on the magnitudes of the force applied.
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Effects of cytokines on prostaglandin E and cAMP levels in human periodontal ligament fibroblasts in vitro

Abstract

Dent. Clin. North Am.

Trends Biochem. Sci.

Clin. Immunol. Immunopath.

Prostaglandins

Archs Biochem. Biophys.

J. biol. Chem.

Cell. Immunol.

J. biol. Chem.

J. biol. Chem.

Overlapping polypeptide induction in human fibroblasts in response to treatment with interferon-α, interferon-γ, interleukin 1α, interleukin 1β, and tumor necrosis factor

J. Immunol.

Dissociation of bradykinin-induced prostaglandin formation from phosphatidylinositol regulation of phospholipase A2

Prostaglandin F2a is associated with alveolar bone cells: immunohistochemical evidence utilizing monoclonal antibodies

Biology of interleukin-1

FASEB J.

Interleukin-1 and its receptor

CRC Crit. Rev. Immunol.

Synergistic stimulation of fibroblast prostaglandin production by recombinant interleukin 1 and tumor necrosis factor

J. Immunol.

An extension of Box's results on the use of the F distribution in multivariate analysis

Ann. Math. Stat.

A protein binding assay for adenosine 3′,5′-monophosphate

Do the interferons act singly or in combination?

J. Interferon Res.

Neutrophil release after injections of endotoxins of leukocytes endogeneous mediators into rats

J. Retic. Soc.

Dissociation of bradykinin-induced prostaglandin formation from phosphatidylinositol regulation of phospholipase A₂

Prostaglandin F_2a is associated with alveolar bone cells: immunohistochemical evidence utilizing monoclonal antibodies