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Salmeterol with fluticasone enhances the suppression of IL-8 release and increases the translocation of glucocorticoid receptor by human neutrophils stimulated with cigarette smoke

By E. Mortaz, M.V. Rad, M. Johnson, D. Raats, F.P. Nijkamp and G. Folkerts


The combination of inhaled corticosteroids and\ud long-acting β2-adrenoceptor agonists is increasingly used\ud in chronic obstructive pulmonary disease (COPD). Recently,\ud we have demonstrated that combination of salmeterol\ud and fluticasone propionate (FP) additionally suppress the\ud production of IL-8 by human monocyte. In this study, the\ud molecular mechanism behind the effectiveness of this\ud combination therapy is investigated in human neutrophils.\ud Human neutrophils were preincubated with salmeterol or\ud FP or the combination. The amount of interleukin-8 (IL-8),\ud elastase and matrix metalloproteinases (MMP)-2 and -9\ud releases, and reactive oxygen species (ROS) generation and\ud expression of MAP kinase phosphatase (MKP-1) and\ud glucocorticoid receptor (GR) were determined. Cigarette\ud smoke medium (CSM) induces an increased expression of\ud CXC receptors and the production of ROS that may explain\ud the strong production of IL-8 by neutrophils. The expression\ud of CXC receptors, the production of ROS, and the\ud release of elastase and MMP-2 and -9 were not influenced by salmeterol, FP, or the combination. Interestingly, the\ud combination therapy had an additive suppressive effect on\ud the CSM-induced production of IL-8. The latter could be\ud explained by an increased mRNA expression of MKP-1,\ud the GR and an increased translocation of the GR to the\ud nucleus. This leads eventually to suppression of both the NF-κB and MAPK pathways and, hence, to less IL-\ud 8 production by the neutrophil. These data are in support\ud for the use of a combination therapy in COPD patients

Topics: Farmacie, Glucocorticoids, Neutrophil, Chemokine
Year: 2008
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