Impaired Endotoxin Tolerance Induction in Patients with Familial Mediterranean Fever

Abstract

Objective: To investigate periodic disturbances in proinflammatory activation of neutrophils and monocytes in patients with familial Mediterranean fever (FMF) both during an attack and in remission. Methods: 20 FMF patients, who were naive to colchicine treatment and did not have amyloidosis, and 10 patients with Behçet’s disease (BD) were enrolled in this study. Phagocytosis, respiratory burst, CD11a/CD18 expression and intracellular cytokine synthesis were determined by flow cytometry. Endotoxin tolerance induction was defined by a reduced capacity of monocytes to respond to lipopolysaccharide (LPS) activation following a first exposure to LPS. Results:In FMF patients, we observed upregulation of neutrophil and monocyte phagocytic activity and oxidative burst during remission and downregulation of phagocytic activity and stimulus-dependent oxidative burst during an attack. A comparative analysis of oxidative burst has revealed that while the neutrophil population shows a certain periodicity in the increase (during remission) and decrease (during attacks) in the spontaneous and inducible respiratory burst, periodicity in the monocyte population is very poor. In addition, LPS-induced oxidative burst and CD11a/CD18 integrin surface expression is higher in patients during an attack compared to patients in remission. The induction of homologous tolerance of monocytes to the repeated action of LPS is observed in FMF patients during an attack, normal donors and patients with BD, whereas monocytes from patients in remission failed to induce LPS homologous tolerance and exhibited heightened sensitivity to bacterial endotoxin. We found that colchicine is able to restore impaired LPS homologous tolerance induction in FMF patients in remission upon increased synthesis of IL-4 in FMF patient monocytes. Conclusion: Chronic inflammation during FMF is characterized by periodic changes in monocyte and neutrophil activation and heightened sensitivity to endotoxin, which is associated with the episodic nature of FMF. Increased endotoxin sensitivity in the period of remission could result from a shift in the monocyte activation program from ‘alternatively’ into ‘classically’ activated monocytes, which may have important implications for the treatment of FMF.

Diminished IL-10 production is Associated with Impaired Versatility of Monocytes in Familiar Mediterranean Fever

“…Previously, we had found that colchicine is able to restore impaired LPS-homologous tolerance induction (assayed by flow cytometry of monocytes, intracellularly synthesizing TNF-α), in FMF patients upon increasing the intracellular IL-4 synthesis and monocyte "alternative" activation [9]. In this study we observed that colchicine increased both IL-10 and IL-1β production by monocytes obtained from ND and FMF patients.…”

“…Endotoxin tolerance was monitored by measuring the production of IL-1β, IL-10, IFN-γ and TNF-α by monocytes in response to LPS after preincubation in the presence or absence of two doses of LPS [9]. Monocytes at 5 ×10 5 cells/ml density were cultured for 18 h in the presence or absence of 100 ng/ml LPS or either with 2 μg/ml colchicine or 2.5 μg/ml PGN or 5 μg/ml MDP or 10 ng/ml recombinant IL-4.…”

“…Endotoxin tolerance is thought to limit the inflammatory response induced during infection, and protects the host from developing shock caused by the excessive production of inflammatory cytokines by monocytes and macrophages [8]. Recently, we have shown that induction of monocyte homologous endotoxin tolerance occurs during an FMF attack, whereas monocytes from patients in the attack-free period fail to induce LPS tolerance and exhibit heightened sensitivity to bacterial endotoxin [9,10]. Impaired LPS tolerance induction in attack-free FMF patients correlates with both the increased LPS-induced pro-inflammatory cytokine synthesis polarization and the different time course pattern of LPS-induced changes on monocytic surface expression of CD14, CD11a/CD18 and CD11b co-receptors.…”

Engaging anti-inflammatory mechanisms and triggering inflammatory effector apoptosis during Familial Mediterranean Fever attack

“…Although we ascertained that increased endotoxin sensitivity in an attack-free period could be a result of a shift in monocyte activation program from "alternatively'' into ''classically" activated [22], the precise mechanisms that could explain aberrant endotoxin tolerance and resolution of infl ammation in FMF are entirely unknown. According to the dynamic view of monocyte activation that integrates cell capacity to switch from one activated state to another, a shift in monocyte activation program may cause resolution of infl ammation without new monocyte recruitment into the infl ammatory site [23].…”

“…Here we investigated homologous and heterologous endotoxin tolerance induction and endotoxin-induced monocyte apoptosis in FMF patients during attack and attack-free periods using the whole blood cell culture technique that preserves blood microenvironment, reduces the risk of contamination, pre-activation, or selective depletion or enrichment of cell subsets [22]. We also used a pharmacological approach to study effects of colchicine (Col) and iodine-lithium-adextrin (ILaD) upon FMF monocytes, as our earlier studies revealed their high potential for inducing homo-and crossendotoxin tolerance and intracellular cytokine synthesis polarization of monocytes during Behçet's disease [25].…”