RESUMO
The mRNAs of most inflammatory mediators are short-lived due to AU-rich elements (AREs) in their 3'-untranslated regions. AREs ensure a low basal level of expression during homeostasis and a transient nature of expression during the inflammatory response. Here, we report that the mRNA of the pro-inflammatory chemokine IL-8, which contains an archetypal ARE, is unexpectedly constitutively abundant and highly stable in primary human monocytes and macrophages. Using the pre-monocyte-like THP-1 cell line that can differentiate into macrophage-like cells, we show that a low level of unstable IL-8 mRNA in undifferentiated cells (half-life<30 min) becomes constitutively elevated and the mRNA is dramatically stabilized in differentiated THP-1 cells with a half-life of more than 15 h similar to primary monocytes and macrophages. In contrast, the level and stability of TNF-α mRNA also containing an ARE is only slightly affected by differentiation; it remains low and unstable in primary macrophages and differentiated THP-1 cells with an estimated half-life of less than 20 min. This differentiation-dependent stabilization of IL-8 mRNA is p38 MAPK-independent and is probably coupled with reduced protein translation. Reporter assays in THP-1 cells suggest that the ARE alone is not sufficient for the constitutive stabilization in macrophage-like cells and imply an effect of the natural biogenesis of the transcript on the stabilization of the mature form. We present a novel, cell type-dependent sustained stabilization of an ARE-containing mRNA with similarities to situations found in disease.
Assuntos
Interleucina-8/genética , Interleucina-8/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Elementos Ricos em Adenilato e Uridilato/fisiologia , Diferenciação Celular , Linhagem Celular Tumoral , Dactinomicina/farmacologia , Células HeLa , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico/farmacologia , Ésteres de Forbol/farmacologia , Estabilidade de RNA , Fator de Necrose Tumoral alfa/genéticaRESUMO
The prevalence of allergic airway diseases such as asthma and rhinitis has increased dramatically to epidemic proportions worldwide. Besides air pollution from industry derived emissions and motor vehicles, the rising trend can only be explained by gross changes in the environments where we live. The world economy has been transformed over the last 25 years with developing countries being at the core of these changes. Around the planet, in both developed and developing countries, environments are undergoing profound changes. Many of these changes are considered to have negative effects on respiratory health and to enhance the frequency and severity of respiratory diseases such as asthma in the general population. Increased concentrations of greenhouse gases, and especially carbon dioxide (CO2), in the atmosphere have already warmed the planet substantially, causing more severe and prolonged heat waves, variability in temperature, increased air pollution, forest fires, droughts, and floods - all of which can put the respiratory health of the public at risk. These changes in climate and air quality have a measurable impact not only on the morbidity but also the mortality of patients with asthma and other respiratory diseases. The massive increase in emissions of air pollutants due to economic and industrial growth in the last century has made air quality an environmental problem of the first order in a large number of regions of the world. A body of evidence suggests that major changes to our world are occurring and involve the atmosphere and its associated climate. These changes, including global warming induced by human activity, have an impact on the biosphere, biodiversity, and the human environment. Mitigating this huge health impact and reversing the effects of these changes are major challenges. This statement of the World Allergy Organization (WAO) raises the importance of this health hazard and highlights the facts on climate-related health impacts, including: deaths and acute morbidity due to heat waves and extreme meteorological events; increased frequency of acute cardio-respiratory events due to higher concentrations of ground level ozone; changes in the frequency of respiratory diseases due to trans-boundary particle pollution; altered spatial and temporal distribution of allergens (pollens, molds, and mites); and some infectious disease vectors. According to this report, these impacts will not only affect those with current asthma but also increase the incidence and prevalence of allergic respiratory conditions and of asthma. The effects of climate change on respiratory allergy are still not well defined, and more studies addressing this topic are needed. Global warming is expected to affect the start, duration, and intensity of the pollen season on the one hand, and the rate of asthma exacerbations due to air pollution, respiratory infections, and/or cold air inhalation, and other conditions on the other hand.