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oai:gupea.ub.gu.se:2077/219442013-04-23T15:10:34Zcom_2077_283com_2077_17com_2077_10556col_2077_543col_2077_310col_2077_10557

Silverpil, Elin 2010-05-11T07:23:26Z 2010-05-11T07:23:26Z 2010-05-11T07:23:26Z 978-91-628-8109-2 http://hdl.handle.net/2077/21944 IL-17 orchestrates the accumulation of neutrophils to sites of infection and the release of microbicidal substances, and therefore plays a critical role in the innate immune response to infection. IL-17 is also involved in certain chronic inflammatory diseases in which dysfunctional control of neutrophil accumulation and turnover constitutes an important pathogenic factor. This pro-inflammatory potential of IL-17 in host defence and in inflammatory diseases has been studied extensively. However, there is now also published evidence that IL-17 has more complex actions, including inflammation-resolving potential under certain conditions. With this in mind, the aims of this thesis were to investigate endogenous and exogenous methods to regulate the production of IL-17 and to elucidate the role that IL-17 plays in resolving ongoing inflammation. More specifically, we looked at whether the cells in the lung produce IL-17 after exposure to lipopolysaccharide (LPS) from the Gram-negative Escherichia coli bacteria, and whether anti-inflammatory pharmacotherapies could be used to regulate the production of IL-17 in these cells. We also examined whether IL-17 contributes to neutrophil turnover through the regulation of macrophage phagocytosis of apoptotic neutrophils. Finally, we investigated whether IL-17 down-regulates the release of the upstream regulator IL-23. We found that LPS induced sustained IL-17 production and release from T cells that reside in lung tissue and that are recruited to the bronchoalveolar space in a mouse model of acute inflammation in vivo. In addition, population of cells other than T cells contributed to IL-17 production in the lung tissues and in the bronchoalveolar space. LPS-induced IL-17 production from T cells in lung tissues and in the bronchoalveolar space was inhibited by the anti-inflammatory drug dexamethasone. Furthermore, we found that IL-17 stimulated macrophage phagocytosis of apoptotic neutrophils and particles, and induced neutrophil apoptosis in an in vitro study on isolated murine and human cells. Finally, we found that that IL-17 inhibited the release of the upstream regulator IL-23, both in the bronchoalveolar space in mice in vivo and in isolated human cells of the monocyte lineage. A major finding is that the production of IL-17 can be regulated exogenously by anti-inflammatory drugs and endogenously by an IL-17-induced feedback loop, which, in turn, may protect against excessive, IL-23-induced IL-17 signalling. In addition, we demonstrate that IL-17 has both pro-inflammatory and inflammation-resolving actions; IL-17 accumulates neutrophils after stimulation with LPS, while it also induces the phagocytosis of apoptotic neutrophils, thereby controlling the total turnover of neutrophils. That IL-17 induces the apoptosis of neutrophils and increases the phagocytosis of these cells indicates a potentially valuable strategy to mitigate conditions in which necrotic neutrophils are an important contributor to severe and sometimes life-threatening conditions, such as chronic lung allograft rejection and acute respiratory distress syndrome. eng I. Prause O, Bossios A, Silverpil E, Ivanov S, Bozinovski S, Vlahos R, Sjöstrand M, Anderson GP, Lindén A. IL-17-producing T lymphocytes in lung tissue and in the bronchoalveolar space after exposure to endotoxin from Escherichia coli in vivo -effects of anti-inflammatory pharmacotherapy. Pulm Pharmacol Ther. 2009:3;199-207 ::pmid::19121406 II. Silverpil E, Glader P, Hansson M, Lindén A. Impact of interleukin-17 on macrophage phagocytosis of apoptotic neutrophils and particles. Inflammation 2010. In press, e-published ahead of print ::pmid::20339909 III. Silverpil E, Glader P, Henningsson L, Jirholt P, Hansson M, Iwakura Y, Gjertsson I, Lindén A. An inhibitory role for IL-17 in the release of IL-23 during airway inflammation. Manuscript in preparation Respiratory medicine Lung IL-17 IL-23 Macrophages Neutrophils T cells Apoptosis Phagocytosis Airways Modulatory role of IL-17 in airway inflammation text Doctoral thesis Doctor of Philosophy (Medicine) Elin.Silverpil@gu.se University of Gothenburg. Sahlgrenska Academy Institute of Medicine. Department of Internal Medicine Torsdagen den 27 maj 2010, kl. 13:00. Föreläsningssalen, våning 3, Guldhedsgatan 10A, Göteborg 2010-05-27 SA open.access