Abstract
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.
Highlights
Familial Mediterranean fever (FMF) is a systemic relapsing autoinflammatory disorder, heritable as an autosomal recessive trait, which is caused by various mutations in the gene MEFV
IL-10 and IL-1β concentration in serum samples was measured in 43 ND and 46 FMF patients
We found that the serum IL-1β is not detectable either in ND or in FMF
Summary
Familial Mediterranean fever (FMF) is a systemic relapsing autoinflammatory disorder, heritable as an autosomal recessive trait, which is caused by various mutations in the gene MEFV. This gene encodes a protein called pyrin, expressed primarily on the innate immune system cells, including neutrophils, and cytokine-activated monocytes [1,2,3]. Macrophages from mice expressing truncated pyrin similar to FMF patients – exhibit heightened sensitivity to bacterial lipopolysaccharide (LPS), produce more active caspase-1 and IL-1β and show resistance to cytokine- and LPS-induced apoptosis [5,6]. Enhancement of LPS-induced apoptosis of neutrophils is observed in FMF patients, which is further confirmed by the fact that neutrophils from FMF patients previously unexposed to Salmonella enteritidis exhibited heightened
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