Rôles fibrogéniques de l'interleukine-4 dans l'asthme

Abstract

L'asthme est caractérisé par un état inflammatoire orchestré par le lymphocyte Th2. Ce dernier se retrouve dans la muqueuse bronchique près des fibroblastes. Cette proximité rend possible la communication entre ces types cellulaires par le biais des cytokines, telle l'interleukine-4 (IL-4). Nous avons émis l'hypothèse que l'IL-4 peut moduler, en faveur d'un processus fibrotique, la synthèse et la dégradation du collagène par les fibroblastes bronchiques. Des cultures primaires de fibroblastes bronchiques isolés de sujets asthmatiques très légers et de sujets normaux ont été stimulées par l'IL-4; en mesurant l'expression de l'ARNm, la synthèse protéique et l'activité du promoteur pour le procollagène Iα1, nous avons démontré que l'IL-4 stimule positivement la transcription du procollagène Iα1. L'IL-4 induit cet effet en régulant positivement Sp1 et négativement AP-1. Également, l'influence de l'IL-4 sur la balance TIMP-2/MMP-2 est en faveur d'un processus profibrotique. Nos résultats confirment donc le rôle profibrogénique de l'IL-4 dans l'asthme.

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Asthma is characterized by an inflammatory state orchestrated by the Th2 lymphocyte. The latter is found in the bronchial mucosa near the fibroblasts. This proximity makes communication possible between these cell types through cytokines, such as interleukin-4 (IL-4). We hypothesized that IL-4 can modulate, in favor of a fibrotic process, the synthesis and degradation of collagen by bronchial fibroblasts. Primary cultures of bronchial fibroblasts isolated from very mild asthmatic subjects and normal subjects were stimulated with IL-4; By measuring mRNA expression, protein synthesis, and promoter activity for procollagen Iα1, we demonstrated that IL-4 positively stimulates procollagen Iα1 transcription. IL-4 mediates this effect by positively regulating Sp1 and negatively regulating AP-1. Also, the influence of IL-4 on the TIMP-2/MMP-2 balance is in favor of a profibrotic process. Our results therefore confirm the profibrogenic role of IL-4 in asthma.