Abstract
ABSTRACTBackground: Cyclic dinucleotides (cyclic di-guanosine monophosphate (c-di-GMP) and cyclic di-adenosine monophosphate (c-di-AMP)) and lipopolysaccharides (LPS) are pathogen-associated molecular patterns (PAMPs). Individual impacts of PAMPs on immune system have been evaluated, but simultaneous actions of multiple PAMPs have not been studied. Objective: Examination the effects of cyclic dinucleotides and Porphyromonas gingivalis LPS on gingival epithelial cytokine response. Methods: Human gingival keratinocytes (HMK) were incubated with 1, 10, and 100 µM concentrations of c-di-GMP and c-di-AMP, either in the presence or absence of P. gingivalis LPS. Intra- and extracellular levels of interleukin (IL)-1β, IL-8, IL-1Ra, monocyte chemoattractant protein (MCP)-1, and vascular endothelial growth factor (VEGF), were measured using the Luminex technique. Results: LPS decreased extracellular IL-8 levels, while the presence of c-di-AMP inhibited this effect. Incubating HMK cells with c-di-AMP (alone or with LPS) elevated the extracellular level of MCP-1. Extracellular VEGF level increased when cells were incubated with LPS and c-di-GMP together, or with c-di-AMP alone. LPS and c-di-AMP suppressed intracellular IL-1β levels. The c-di-AMP elevated intracellular levels of IL-1Ra. Conclusion: c-di-AMP and, to a lesser extent, c-di-GMP regulate keratinocyte cytokine response, either as an aggregator or as a suppressor of LPS, depending on the cytokine type.
Highlights
Cyclic dinucleotides are important secondary signaling molecules in bacteria [1]
No significant changes were observed in intracellular levels of IL-8 when Human gingival keratinocytes (HMK) cells were incubated with LPS, c-di-GMP, or c-di-AMP (Figure 2(a,b))
We demonstrated that c-di-AMP enhances monocyte chemoattractant protein (MCP)-1 and IL-1Ra and suppresses IL-1β, as well as neutralizes the LPS-inhibited IL-8 expression
Summary
Cyclic dinucleotides are important secondary signaling molecules in bacteria [1]. In Gram-negative bacteria, cyclic di-guanosine monophosphate (c-di-GMP) is involved in central bacterial processes, such as virulence, stress survival, motility, metabolism, biofilm formation, and differentiation [2]. The presence of cdi-GMP, or its binding proteins, has been demonstrated in some periodontitis-associated bacteria, including Porphyromonas gingivalis, Treponema denticola, and Selenomonas noxia [6,7,8,9]. These secondary signaling molecules have been found to regulate the oxidative response, extracellular polysaccharide matrix production, and biofilm formation of cariogenic Streptococcus mutans [10,11]. Extracellular VEGF level increased when cells were incubated with LPS and c-di-GMP together, or with c-di-AMP alone. Conclusion: c-di-AMP and, to a lesser extent, c-di-GMP regulate keratinocyte cytokine response, either as an aggregator or as a suppressor of LPS, depending on the cytokine type
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