| dc.description.abstract | Chronic bronchitis, chronic obstructive pulmonary disease (COPD), bronchial asthma and cystic fibrosis are common clinical disorders all characterized by airway neutrophilia. By releasing proteolytic enzymes and free oxygen radicals, neutrophils can contribute to the main features of these diseases such as airway obstruction, hypersecretion and remodelling. It is known that airway neutrophilia can be controlled by activated T-cells. However, the mechanisms behind this effect are not fully understood. The aim of this work was to evaluate whether the recently characterized T-cell cytokine, IL-17, can contribute to the neutrophilic airway inflammation and, if so, which mechanisms are involved. The role of IL-17 was evaluated using in vitro culture of human bronchial epithelial cells (HBE) and isolated human and rat neutrophils, in vivo rat airway model, as well as analysis of samples from human subjects with induced airway neutrophilia.In vitro, in HBE cells, treatment with IL-17 caused an increased production of the major neutrophil chemoattractant, IL-8 which, as indicated in neutrophil chemotaxis assay, was functionally significant. However, IL-17 had no direct effect on neutrophil chemotaxis in vitro. In rats, in vivo, intratracheal installation of IL-17 caused a selective increase in airway neutrophil numbers, which was inhibited by an antibody (Ab) against murine analogue for IL-8, MIP-2. The effect of IL-17 was inhibited by a specific IL-17 Ab and by glucocorticoids both in vivo and in vitro indicating a protein specific and steroid sensitive mechanism. In conclusion, the first part of the work implies that IL-17 may recruit neutrophils into the airways indirectly, via the release of C-X-C chemokines such as IL-8 (in humans) and MIP-2 (in rats) from cells present in the airways.To determine whether IL-17 can, in addition to neutrophil recruitment into the airways, also activate the airway neutrophils, the activity of myeloperoxidase and neutrophil elastase was measured in rat airways after intratracheal treatment with IL-17. Both the activity of elastase as well as myeloperoxidase was increased in bronchoalvelar lavage fluid (BAL) from IL-17 treated rats. However, in vitro, IL-17 had no effect on activation of isolated rat neutrophils, indicating that IL-17 activates the airway neutrophils via an indirect mechanism, probably by releasing neutrophil-mobilizing cytokines from cells present in the airways such as bronchial epithelial cells.Since cytokine production in bronchial epithelial cells is controlled by certain protein kinases, the third part of the work focused on the intracellular mechanisms behind IL-17 induced neutrophil-mobilizing cytokine production. IL-17 induced IL-6 and IL-8 production in HBE cells was studied using inhibitors to the central intracellular regulators, the mitogen activated protein (MAP) kinases. This part of the work indicates a major role for p38 and ERK MAP kinases in IL-17 induced IL-6 and IL-8 production in HBE cells. The last part of the work aimed to determine whether IL-17 can be released in human airways before and after exposure of healthy volunteers to airborne swine dust. Swine dust exposure resulted in a significant increase in airway IL-17 levels as well as the levels of neutrophil-mobilizing cytokines and the numbers of neutrophils in the airways. However, in this model of airway inflammation, we were unable to detect any statistically significant relationship between the levels of IL-17 and neutrophil-mobilizing cytokines or the levels of IL-17 and numbers of airway neutrophils. Taken together, the referred work indicates that the T-cell cytokine, IL-17, can play a role in T-cell controlled neutrophilic airway inflammation. Whether and how IL-17 contributes to the development of airway neutrophilia in certain clinical diseases requires further investigation. | en |
