Background: 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.