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1.
J Allergy Clin Immunol ; 131(6): 1635-43, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23006543

ABSTRACT

BACKGROUND: The exact pathogenesis of the pediatric disorder periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome is unknown. OBJECTIVES: We hypothesized that PFAPA might be due to dysregulated monocyte IL-1ß production linked to genetic variants in proinflammatory genes. METHODS: Fifteen patients with PFAPA syndrome were studied during and outside a febrile episode. Hematologic profile, inflammatory markers, and cytokine levels were measured in the blood. The capacity of LPS-stimulated PBMCs and monocytes to secrete IL-1ß was assessed by using ELISA, and active IL-1ß secretion was visualized by means of Western blotting. Real-time quantitative PCR was performed to assess cytokine gene expression. DNA was screened for variants of the MEFV, TNFRSF1A, MVK, and NLRP3 genes in a total of 57 patients with PFAPA syndrome. RESULTS: During a febrile attack, patients with PFAPA syndrome revealed significantly increased neutrophil counts, erythrocyte sedimentation rates, and C-reactive protein, serum amyloid A, myeloid-related protein 8/14, and S100A12 levels compared with those seen outside attacks. Stimulated PBMCs secreted significantly more IL-1ß during an attack (during a febrile episode, 575 ± 88 pg/mL; outside a febrile episode, 235 ± 56 pg/mL; P < .001), and this was in the mature active p17 form. IL-1ß secretion was inhibited by ZYVAD, a caspase inhibitor. Similar results were found for stimulated monocytes (during a febrile episode, 743 ± 183 pg/mL; outside a febrile episode, 227 ± 92 pg/mL; P < .05). Genotyping identified variants in 15 of 57 patients, with 12 NLRP3 variants, 1 TNFRSF1A variant, 4 MEFV variants, and 1 MVK variant. CONCLUSION: Our data strongly suggest that IL-1ß monocyte production is dysregulated in patients with PFAPA syndrome. Approximately 20% of them were found to have NLRP3 variants, suggesting that inflammasome-related genes might be involved in this autoinflammatory syndrome.


Subject(s)
Fever/metabolism , Interleukin-1beta/biosynthesis , Lymphadenitis/metabolism , Monocytes/metabolism , Pharyngitis/metabolism , Stomatitis, Aphthous/metabolism , Adolescent , Adult , Aged , Child , Female , Fever/genetics , Fever/immunology , Genetic Variation , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation Mediators/blood , Interleukin 1 Receptor Antagonist Protein/metabolism , Leukocyte Count , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/immunology , Lymphadenitis/genetics , Lymphadenitis/immunology , Male , Middle Aged , Monocytes/immunology , Neutrophils , Pharyngitis/genetics , Pharyngitis/immunology , Stomatitis, Aphthous/genetics , Stomatitis, Aphthous/immunology , Syndrome , Young Adult
2.
Arthritis Rheum ; 63(2): 422-33, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21279999

ABSTRACT

OBJECTIVE: To determine the mechanisms involved in inflammatory responses to octacalcium phosphate (OCP) crystals in vivo. METHODS: OCP crystal-induced inflammation was monitored using a peritoneal model of inflammation in mice with different deficiencies affecting interleukin-1 (IL-1) secretion (IL-1α(-/-) , IL-1ß(-/-) , ASC(-/-) , and NLRP3(-/-) mice) or in mice pretreated with IL-1 inhibitors (anakinra [recombinant IL-1 receptor antagonist] and anti-IL-1ß). The production of IL-1α, IL-1ß, and myeloid-related protein 8 (MRP-8)-MRP-14 complex was determined by enzyme-linked immunosorbent assay. Peritoneal neutrophil recruitment and cell viability were determined by flow cytometry. Depletion of mast cells or resident macrophages was performed by pretreatment with compound 48/80 or clodronate liposomes, respectively. RESULTS: OCP crystals induced peritoneal inflammation, as demonstrated by neutrophil recruitment and up-modulation of IL-1α, IL-1ß, and MRP-8-MRP-14 complex, to levels comparable with those induced by monosodium urate monohydrate crystals. This OCP crystal-induced inflammation was both IL-1α- and IL-1ß-dependent, as shown by the inhibitory effects of anakinra and anti-IL-1ß antibody treatment. Accordingly, OCP crystal stimulation resulted in milder inflammation in IL-1α(-/-) and IL-1ß(-/-) mice. Interestingly, ASC(-/-) and NLRP3(-/-) mice did not show any alteration in their inflammation status in response to OCP crystals. Depletion of the resident macrophage population resulted in a significant decrease in crystal-induced neutrophil infiltration and proinflammatory cytokine production in vivo, whereas mast cell depletion had no effect. Finally, OCP crystals induced apoptosis/necrosis of peritoneal cells in vivo. CONCLUSION: These data indicate that macrophages, rather than mast cells, are important for initiating and driving OCP crystal-induced inflammation. Additionally, OCP crystals induce IL-1-dependent peritoneal inflammation without requiring the NLRP3 inflammasome.


Subject(s)
Bone Substitutes/toxicity , Calcium Phosphates/toxicity , Carrier Proteins/metabolism , Interleukin-1/metabolism , Peritonitis/chemically induced , Animals , Bone Density Conservation Agents/pharmacology , Cell Survival/drug effects , Clodronic Acid/pharmacology , Crystallization , Disease Models, Animal , Female , Injections, Intraperitoneal , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/pathology , Male , Mast Cells/drug effects , Mast Cells/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein , Neutrophils/drug effects , Neutrophils/pathology , Peritoneum/drug effects , Peritoneum/pathology , Peritonitis/metabolism , Peritonitis/pathology , p-Methoxy-N-methylphenethylamine/pharmacology
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