sirolimus and Familial-Mediterranean-Fever

Mutations in

Topics: Animals; Apoptosis; Bacterial Proteins; Bacterial Toxins; Cells, Cultured; Disease Models, Animal; Enterotoxins; Familial Mediterranean Fever; Humans; Inflammasomes; Macrophages; Mice; Mice, Knockout; Mutation; Necroptosis; Peritonitis; Phosphorylation; Primary Cell Culture; Pyrin; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcriptional Activation; Up-Regulation

Familial Mediterranean fever (FMF) inflammatory attacks are often triggered by metabolic or physical stress. mTOR signaling and autophagy modulate cellular responses to metabolic danger signals. In this study, we investigated the implication of mTOR inhibition and autophagy in FMF pathophysiology. mTOR inhibition induced MEFV gene expression in polymorphonuclear cells (PMNs) from healthy individuals, whereas it had no effect on PMNs from attack-free FMF patients. A significant reduction in pyrin levels in PMNs from FMF patients after mTOR inhibition was also observed. Pyrin levels in control PMNs remained unaffected. Moreover, the basal autophagic status in PMNs from FMF patients was reduced, as indicated by the lower LC3B-II/I ratio and ATG mRNA expression levels. However, mTOR inhibition had similar effects on the induction of autophagy in the two groups. The differential pyrin expression after metabolic stress induction and the impaired basal autophagy suggest a potential role in the triggering of FMF attacks.

Topics: Autophagy; Cysteine Endopeptidases; Cytoskeletal Proteins; Familial Mediterranean Fever; Gene Expression; Humans; Mutation; Neutrophils; Phenotype; Pyrin; RNA, Messenger; Signal Transduction; Sirolimus; Stress, Physiological; TOR Serine-Threonine Kinases