RESUMO
The lipoxin A4 receptor FPR2/ALX plays an important part in host defense and inflammation. The receptor binds structurally diverse agonistic ligands, which mainly regulate chemotaxis and activation of leukocytes. However, little is known about the promoter region of the FPR2/ALX gene and its transcriptional regulation in leukocytes. We identified two TATA-less promoter regions, separated by 224 bp, that drive the expression of FPR2/ALX in macrophages. Both promoter regions increased transcription in a reporter assay, and the basal transcription factors OCT1 and SP1 were shown to bind the first and the second promoter, respectively, and to transactivate transcription. Although monocytes expressed high levels of FPR2/ALX mRNA from the second promoter region, differentiation into macrophages abrogated FPR2/ALX expression. Stimulation of macrophages with a set of cytokines revealed that only IFN-γ and LPS increased FPR2/ALX expression from the first promoter to levels similar to those detected in monocytes. The upregulation by IFN-γ is in part mediated by the interaction of IFN regulatory factor 1 with an IFN-responsive sequence element transcription factor binding site located in the first promoter region of the FPR2/ALX gene. However, this upregulation on the mRNA level did not translate into FPR2/ALX protein expression in macrophages owing to reduced translation of the longer mRNA from the first promoter. In contrast, FPR2/ALX mRNA transcribed from the second promoter was translated into surface expression of FPR2/ALX in monocytes. These data support a model in which FPR2/ALX plays a role in chemotaxis and activation of monocytes; however, they also suggest that its function in resident tissue macrophages is limited.
Assuntos
Macrófagos/metabolismo , Monócitos/metabolismo , Regiões Promotoras Genéticas , Receptores de Formil Peptídeo/genética , Receptores de Lipoxinas/genética , Sequências Reguladoras de Ácido Nucleico , Regiões 5' não Traduzidas/genética , Sítios de Ligação/genética , Quimiotaxia de Leucócito , Regulação da Expressão Gênica , Humanos , Fator Regulador 1 de Interferon/metabolismo , Interferon gama/imunologia , Lipopolissacarídeos/imunologia , Macrófagos/citologia , Dados de Sequência Molecular , Monócitos/citologia , Transportador 1 de Cátions Orgânicos/metabolismo , RNA Mensageiro/biossíntese , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo , Fator de Transcrição Sp1/metabolismo , Sítio de Iniciação de Transcrição , Transcrição Gênica , Ativação TranscricionalRESUMO
Asthma is a chronic pulmonary disorder that is characterized by airway inflammation and bronchial hyperreactivity. Several genetic loci have been associated with asthma, and some of these associations have been replicated in independent studies. However, larger population-based replication studies for the association of short tandem repeat (STR) polymorphisms with asthma are limited. In this study, we investigated the association of STR polymorphisms in genes encoding mast cell chymase (CMA1), uteroglobin (UGB), tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) with asthma and atopic phenotypes in the large population-based Swiss Cohort Study SAPALDIA. Our results show that the STR polymorphism in the CMA1 gene is associated with asthma and that this association is even stronger with atopic asthma. Similarly, we observed a weak association of the IL-4 2-allele with asthma that tended to be stronger for atopic asthma than for nonatopic asthma. This minor IL-4 2-allele was also associated with higher IgE levels, with a higher risk for a positive skin prick test and with a trend for a higher risk for bronchial hyperresponsiveness. These results support previous findings suggesting a role for CMA1 and IL-4 in atopic asthma and for IL-4 in atopy in general.
Assuntos
Asma/genética , Asma/imunologia , Quimases/genética , Interleucina-4/genética , Repetições de Microssatélites/genética , Adolescente , Adulto , Asma/sangue , Asma/epidemiologia , Asma/fisiopatologia , Hiper-Reatividade Brônquica , Progressão da Doença , Feminino , Estudos de Associação Genética , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Testes Cutâneos , Suíça , Fator de Necrose Tumoral alfa/genética , Uteroglobina/genéticaRESUMO
The 12/15-lipoxygenase plays a janus-role in inflammation with pro-inflammatory and anti-inflammatory effects in cell systems and even opposite effects on atherosclerosis in two different animal species. Screening of the human 15-lipoxygenase (ALOX15) gene detected a polymorphic C to T substitution at position c.-292, which led to three times higher ALOX15 activity in macrophages and showed a trend to be atheroprotective in a small case-control study for coronary artery disease (CAD). A second polymorphism at position c.1693C>T leading to an T560M exchange and an inactive enzyme was recently associated with increased CAD. We now investigated whether these polymorphisms or a certain haplotype of ALOX15 are associated with myocardial infarction (MI) in a case-control subset from the population-based MONIKA/KORA cohort S3. Six polymorphisms in ALOX15 were analyzed in 2629 participants to cover all major haplotypes with a frequency higher than 1% in the Caucasian population. None of the polymorphism was associated with MI but a rare ALOX15 haplotype showed a significant protective effect on the risk for MI (p=0.03). However, none of the polymorphisms or haplotypes was associated with CRP levels. These data suggest that ALOX15 may play a less prominent role during later stages of atherosclerosis involving atherothrombotic mechanisms than eventually during early plaque development.
