The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators

Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever and neutrophil-mediated serosal inflammation. We recentl y identified the gene causing FMF, designated MEFV, and found it to be expr essed in mature neutrophils, suggesting that it functions as an inflammator y regulator. To facilitate our understanding of the normal function of MEFV , we extended our previous studies, MEFV messenger RNA was detected by reve rse transcriptase-polymerase chain reaction in bone marrow leukocytes, with differential expression observed among cells by in situ hybridization. CD3 4 hematopoietic stem-cell cultures induced toward the granulocytic lineage expressed MEFV at the myelocyte stage, concurrently with lineage commitment . The prepromyelocytic cell line HL60 expressed MEFV only at granulocytic a nd monocytic differentiation. MEN was also expressed in the monocytic cell lines U937 and THP-1. Among peripheral blood leukocytes, MEFV expression wa s detected in neutrophils, eosinophils, and to varying degrees, monocytes. Consistent with the tissue specificity of expression, complete sequencing a nd analysis of upstream regulatory regions of MEN revealed homology to myel oid-specific promoters and to more broadly expressed inflammatory promoter elements. In vitro stimulation of monocytes with the proinflammatory agents interferon (IFN) gamma, tumor necrosis factor, and lipopolysaccharide indu ced MEFV expression, whereas the antiinflammatory cytokines interleukin (IL ) 4, 11-10, and transforming growth factor beta inhibited such expression. Induction by IFN-gamma occurred rapidly and was resistant to cycloheximide, IFN-alpha also induced MEFV expression. In granulocytes, MEN was up-regula ted by IFN-gamma and the combination of IFN-alpha and colchicine. These res ults refine understanding of MEFV by placing the gene in the myelomonocytic -specific proinflammatory pathway and identifying it as an IFN-gamma immedi ate early gene. (C) 2000 by The American Society of Hematology.