Alendronate regulates cytokine production induced by lipid A through nuclear factor-kappa B and Smad3 activation in human gingival fibroblasts

作者：Tamai R; Sugiyama A; Kiyoura Y^*

来源：Journal of Periodontal Research, 2011, 46(1): 13-20.

DOI：10.1111/j.1600-0765.2010.01302.x

• nitrogen-containing bisphosphonate
• lipid A
• cytokine
• transcription factor

Background and Objective:
Nitrogen-containing bisphosphonates (NBPs) are widely used as anti-bone-resorptive drugs. However, use of NBPs results in inflammatory side-effects, including jaw osteomyelitis. In the present study, we examined the effects of alendronate, a typical NBP, on cytokine production by human peripheral blood mononuclear cells (PBMCs) and gingival fibroblasts incubated with lipid A.
Methods:
The PBMCs and gingival fibroblasts were pretreated with or without alendronate for 24 h. Cells were then incubated in the presence or absence of lipid A for a further 24 h. Levels of secreted human interleukin (IL)-1 beta, IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1) in culture supernatants were measured by ELISA. We also examined nuclear factor-kappa B (NF-kappa B) activation in both types of cells by ELISA. Activation of Smad3 in the cells was assessed by flow cytometry. In addition, we performed an inhibition assay using SIS3, a specific inhibitor for Smad3.
Results:
Pretreatment of PBMCs with alendronate promoted lipid A-induced production of IL-1 beta and IL-6, but decreased lipid A-induced IL-8 and MCP-1 production. In human gingival fibroblasts, alendronate pretreatment increased lipid A-induced production of IL-6 and IL-8, and increased NF-kappa B activation in gingival fibroblasts but not PBMCs stimulated with lipid A. In contrast, alendronate activated Smad3 in both types of cells. Finally, SIS3 inhibited alendronate-augmented IL-6 and IL-8 production by human gingival fibroblasts but up-regulated alendronate-decreased IL-8 production by PBMCs.
Conclusion:
These results suggest that alendronate-mediated changes in cytokine production by gingival fibroblasts occur via regulation of NF-kappa B and Smad3 activity.

• 出版日期2011-2