Abstract
ObjectivePeriodontal disease is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss in severe clinical cases. Interleukin (IL)-6, IL-8, and the chemical mediator prostaglandin E2 (PGE2) are known to play important roles in inflammatory responses and tissue degradation.Recently, we reported that the protein kinase A (PKA) inhibitor H-89 suppresses lipopolysaccharide (LPS)-induced IL-8 production by human gingival fibroblasts (HGFs). In the present study, the relevance of the PKA activity and two PKA-activating drugs, aminophylline and adrenaline, to LPS-induced inflammatory cytokines (IL-6 and IL-8) and PGE2 by HGFs were examined.MethodsHGFs were treated with LPS from Porphyromonas gingivalis and H-89, the cAMP analog dibutyryl cyclic AMP (dbcAMP), aminophylline, or adrenaline. After 24 h, IL-6, IL-8, and PGE2 levels were evaluated by ELISA.ResultsH-89 did not affect LPS-induced IL-6 production, but suppressed IL-8 and PGE2 production. In contrast, dbcAMP significantly increased LPS-induced IL-6, IL-8, and PGE2 production. Up to 10 μg/ml of aminophylline did not affect LPS-induced IL-6, IL-8, or PGE2 production, but they were significantly increased at 100 μg/ml. Similarly, 0.01 μg/ml of adrenaline did not affect LPS-induced IL-6, IL-8, or PGE2 production, but they were significantly increased at concentrations of 0.1 and 1 μg/ml. In the absence of LPS, H-89, dbcAMP, aminophylline, and adrenaline had no relevance to IL-6, IL-8, or PGE2 production.ConclusionThese results suggest that the PKA pathway, and also PKA-activating drugs, enhance LPS-induced IL-6, IL-8, and PGE2 production by HGFs. However, aminophylline may not have an effect on the production of these molecules at concentrations used in clinical settings (8 to 20 μg/ml in serum). These results suggest that aminophylline does not affect inflammatory responses in periodontal disease.
Highlights
Periodontal disease is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss in severe clinical cases
In the absence of LPS, H-89, dibutyryl cyclic AMP (dbcAMP), aminophylline, and adrenaline had no relevance to IL-6, IL-8, or prostaglandin E2 (PGE2) production
These results suggest that the protein kinase A (PKA) pathway, and PKA-activating drugs, enhance LPS-induced IL-6, IL-8, and PGE2 production by human gingival fibroblasts (HGFs)
Summary
Periodontal disease is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss in severe clinical cases. We reported that the protein kinase A (PKA) inhibitor H-89 suppresses LPS-induced IL-8 production by human gingival fibroblasts (HGFs) [5] This finding suggests that the PKA pathway enhances LPS-induced IL-8 production, and that taking PKA-activating drugs results in an increase of inflammatory cytokines production, and further, the exacerbation of periodontal disease. Xanthine derivatives such as theophylline and aminophylline inhibit the cAMPdegrading enzyme phosphodiesterase (PDE), increase intracellular cAMP, and activate the PKA pathway [6] These drugs are clinically used as cardiotonic agents for cardiac failure or as bronchodilator agents for chronic obstructive pulmonary disease. B-adrenergic agonists activate adenylate cyclase, increase intracellular cAMP, and activate the PKA pathway Because withdrawal of these drugs, in particular xanthine derivatives, leads to exacerbation of cardiac failure and chronic obstructive pulmonary disease, withdrawal is difficult in patients having these diseases. There is a need to examine whether these drugs affect the inflammatory responses in periodontal disease
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