Tigran K. Davtyan, Gagik S. Hakobyan, Samvel A. Avetisyan, Anna G. Sukiasyan and Yuri T. Aleksanyan
Purpose: The nature of the heightened endotoxin sensitivity state observed in Familial Mediterranean Fever (FMF) at present remains unknown. To assess the possibility that IL-10 plays a role in setting the inflammatory threshold, we studied IL-10 production by monocytes and dendritic cells as well as endotoxin tolerance induction in FMF patients.
Methods: 46 attack-free FMF patients were included in this study. The production of IL-10 by NLR- or TLRagonist- stimulated monocytes and dendritic cells were assayed either by conventional ELISA or flow cytometry. The versatility of monocytes was studied by measuring the production of IL-10 and IL-1β after stimulation by pro- and anti-inflammatory agents, and after stimulation arrest or a further counter stimulation. Monocyte endotoxin tolerance and cross-tolerance induction were assayed by measuring the production of IL-1β, IL-10, TNF-α and IFN-γ after prestimulation by NLR- or TLR-ligands and after re-stimulation with LPS.
Results: In FMF patients, we observed down-regulation of circulating CD36+ peripheral blood lymphoid cells but not monocytes, constitutively producing IL-10. The production of IL-10 by TLR- and NLR-agonist-stimulated monocytes and dendritic cells declines in FMF patients. Monocytes isolated from FMF patients failed to switch from a pro-inflammatory activated state to anti-inflammatory phenotype and still produce IL-1β but not IL-10, which cause impaired endotoxin tolerance and cross-tolerance induction. The IL-10 production and endotoxin tolerance induction by monocytes and dendritic cells were restored by NOD2- ligand MDP and colchicine treatment.
Conclusion: The reduced IL-10 production was associated with the impaired setting of feedback inhibition of inflammatory response and caused impaired resolution of inflammation and endotoxin tolerance induction.