RESUMO
Recurrences develop in up to 20-50% of patients with acute pericarditis. Although different causes of recurrent pericarditis have been identified, the etiology remains obscure in most cases which are therefore labelled as idiopathic. Autoinflammatory syndromes include familial Mediterranean fever (FMF), due to mutations in the MEFV gene, and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), due to mutations in the TNFRSF1A gene. Recurrent pericarditis is a common feature of both conditions, but it rarely occurs alone. Colchicine is the standard treatment for FMF, while patients with TRAPS do not respond to colchicine therapy, but are responsive to corticosteroids. Based on the proven efficacy of colchicine in preventing polyserositis in FMF, colchicine has been proposed for the treatment of recurrent pericarditis and is able to decrease the recurrence rate. Our aim was to investigate the possible involvement of TNFRSF1A mutations in a group of patients with idiopathic recurrent pericarditis who were refractory to colchicine treatment. Thirty consecutive patients (17 males, 13 females) diagnosed with idiopathic recurrent pericarditis, who were characterized by a poor response to colchicine treatment, were enrolled in the study. Mutations of the TNFRSF1A gene were searched for by amplifying, using polymerase chain reaction (PCR), genomic DNA, and direct sequencing. TNFRSF1A mutations were found in 4 of the 30 patients. None of these 4 patients had a family history of recurrent inflammatory syndromes or history of pericarditis. One of the 4 patients had a novel heterozygous deletion (DeltaY103-R104) and three patients carried a heterozygous low-penetrance R92Q mutation. Our data suggest that TRAPS should be kept in mind in the differential diagnosis of recurrent pericarditis, and mutation analysis of the TNFRSF1A gene should be considered, in addition to MEFV analysis, in patients of Mediterranean origin. A poor response to colchicine treatment and/or a steroid-dependence may be the clue to investigate TNFRSF1A mutations in patients with idiopathic recurrent pericarditis.
Assuntos
Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/genética , Mutação , Pericardite/tratamento farmacológico , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Doença Aguda , Adolescente , Corticosteroides/uso terapêutico , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Proteínas do Citoesqueleto/genética , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/imunologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Pericardite/genética , Pericardite/imunologia , Fenótipo , Reação em Cadeia da Polimerase , Pirina , Recidiva , Fatores de Risco , Síndrome , Falha de Tratamento , Adulto JovemAssuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Adolescente , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Supressores da Gota/uso terapêutico , Humanos , Pirina , SíndromeRESUMO
Initially identified and further developed as inhibitors of cyclooxygenases, nonsteroidal antiinflammatory drugs (NSAIDs) have been more recently shown to bind to and act as agonists of the peroxisome proliferator-activated receptor family of transcription factors. Here we summarize the current knowledge on the functions of the principal targets of NSAIDs and review their role in T and B lymphocytes, with a focus on the molecular mechanisms underlying the effects of NSAIDs on lymphocyte development, activation, differentiation and death.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/fisiologia , Animais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Humanos , Isoenzimas/química , Isoenzimas/fisiologia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/imunologia , Proteínas de Membrana , Modelos Biológicos , Prostaglandina-Endoperóxido Sintases/química , Prostaglandina-Endoperóxido Sintases/fisiologia , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/fisiologiaRESUMO
Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through at least three different transduction routes: Galpha s-mediated stimulation of adenylylcyclase (AC), Galpha q-mediated activation of phospholipase Cbeta (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative role of different pathways in human skin fibroblast proliferation. Using chemical inhibitors and activators of signal transduction, we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two counteracting pathways--an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulated by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time, their point of divergence in mediating PTHrP dual and opposite mitogenic effects.
