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| 2. |
- Ivanov, Stefan, 1974, et al.
(författare)
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Functional relevance of the IL-23-IL-17 axis in lungs in vivo.
- 2007
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Ingår i: American journal of respiratory cell and molecular biology. - 1044-1549. ; 36:4, s. 442-51
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Tidskriftsartikel (refereegranskat)abstract
- It is known that interleukin (IL)-23, an IL-12-family cytokine, can be released by certain antigen-presenting cells in response to bacterial pathogens. Recent in vitro studies indicate that this cytokine stimulates a unique subset of CD4 cells, the T helper cell (Th)17 subset, to produce and release the proinflammatory cytokine IL-17. However, it has not been known whether this is an action of IL-23 per se that has bearing for the early innate response in lungs in vivo and whether there is an IL-23-responsive population of IL-17-producing CD4 cells in the bronchoalveolar space. We now present evidence that IL-23 can be involved in the early innate response to both gram-negative and gram-positive bacterial products in the lungs: Recombinant IL-23 protein per se accumulates inflammatory cells in the bronchoalveolar space in part via endogenous production of IL-17, and this IL-17 production occurs locally in IL-23-responsive CD4 cells. This IL-17 response to IL-23 occurs without any pronounced impact on Th1/Th2 polarization. Moreover, recombinant IL-23 protein increases the local MMP-9 activity, which is generated by neutrophils mainly. CD4 cells in the lungs may thus respond to IL-23 from antigen-presenting cells exposed to gram-negative and gram-positive pathogens and thereby reinforce the early innate response. These findings support that IL-23 and IL-17 form a functionally relevant "immunological axis" in the lungs in vivo.
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| 3. |
- Ivanov, Stefan, 1974, et al.
(författare)
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Interleukin-17 as a drug target in human disease.
- 2009
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Ingår i: Trends in pharmacological sciences. - : Elsevier BV. - 0165-6147. ; 30:2, s. 95-103
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-17 (now synonymous with IL-17A) is an archetype molecule for an entire family of IL-17 cytokines. Currently believed to be produced mainly by a specific subset of CD4 cells, named Th-17 cells, IL-17 is functionally located at the interface of innate and acquired immunity. Specifically, it induces the release of chemokines and growth factors from mesenchymal cells and is now emerging as an important local orchestrator of neutrophil accumulation in several mammalian organs. Furthermore, there is growing evidence that targeting IL-17 signaling might prove useful in a variety of diseases including asthma, Crohn's disease, multiple sclerosis, psoriatric disease and rheumatoid arthritis. Here, we summarize the key aspects of the biology of IL-17 in mammals and scrutinize the potential pharmacological use of targeting IL-17 in humans.
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| 4. |
- Ivanov, Stefan, 1974
(författare)
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Interleukin-17 in models of neutrophilic lung disease
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Several acute or chronic lung disorders like adult respiratory distress syndrome, acute severe asthma, chronic obstructive pulmonary disease, chronic lung allograft rejection and cystic fibrosis, are associated with signs of an excess innate response in the bronchoalveolar space. Neutrophils may play a pathogenic role in these lung diseases by contributing to non-specific bronchial hyperresponsiveness and bronchial hypersecretion, as well as to epithelial damage and tissue remodelling. Previous studies employing stimuli of Gram-negative bacteria in mice have shown that the T-cell cytokine Interleukin (IL)-17 (also named IL-17A) can contribute to accumulation of neutrophils within the bronchoalveolar space. The general aims of this thesis were to determine a cellular source of IL-17 in the human bronchoalveolar space in vivo and to further characterize the role of IL-17 and the IL-17-inducing cytokine IL-23 in neutrophilic lung disease. In study one, severe neutrophilic inflammation in the human bronchoalveolar space was caused by exposure of healthy, non-smoking volunteers to organic dust. The exposure increased IL-17 messenger (m) RNA in bronchoalveolar-lavage (BAL) cells and, because of an intracellular expression of IL-17 protein in lymphoid BAL cells, IL-17 may originate from lymphocytes residing within the bronchoalveolar space. The increased IL-17 mRNA expression was associated with an increased percentage of matrix metalloproteinase (MMP)-9-expressing BAL neutrophils. This is compatible with IL-17 controlling the local proteolytic burden of tissue-degrading enzymes like MMP-9, via its neutrophil-accumulating effect. In study two, sensitized and allergen-challenged mice were pre-treated with a specific anti-IL-17 antibody in order to block endogenous IL-17. We showed that endogenous IL-17 may contribute not only to the accumulation of BAL neutrophils but also to the accumulation of BAL macrophages. IL-17 may serve as a direct chemotactic factor for macrophage precursor cells and as a survival factor for macrophages within the bronchoalveolar space. In addition, we present evidence that IL-17 might control the local proteolytic burden, since blocking endogenous IL-17 decreased the percentage of MMP-9-expressing BAL neutrophils and macrophages. In study three, we determined the impact of the antigen-presenting cells cytokine IL-23 in the innate response of the lungs utilizing stimulation with bacterial structural components as well as with recombinant IL-23 protein. We showed that both Gram-negative and Gram-positive bacterial components promoted the release of IL-23 in lung tissue and BAL fluid. We also demonstrated that short-term stimulation with recombinant IL-23 protein caused accumulation of macrophages and neutrophils in the bronchoalveolar space via endogenous production of IL-17. This production of IL-17 occurred locally in IL-23-responsive CD4 cells. In addition, IL-23 did not seem to markedly affect the Th1 or Th2 polarization of these CD4 cells. Finally, stimulation with recombinant IL-23 protein increased the local MMP-9 activity, which was generated by neutrophils mainly. In conclusion, there are lymphocytes residing within the human bronchoalveolar space, which are capable of producing IL-17. In mice, IL-17 production takes place in IL-23 responsive bronchoalveolar CD4 cells and IL-17 may contribute to the accumulation of both macrophages and neutrophils to the bronchoalveolar space. Thus, the antigen-presenting cell cytokine IL-23 and the Tcell cytokine IL-17 seem to form a functional immunological axis in mouse lungs in vivo. This IL-23-IL-17 axis is involved in the early innate immune response to Gram-negative and Gram-positive bacteria. If similar mechanisms exist in humans, IL-23 and IL-17 may constitute potential pharmacotherapeutical targets in severe lung diseases associated with an excess innate response.
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| 5. |
- Ivanov, Stefan, 1974, et al.
(författare)
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Interleukin-17A mRNA and protein expression within cells from the human bronchoalveolar space after exposure to organic dust
- 2005
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 6, s. 44-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In mice, the cytokine interleukin (IL)-17A causes a local accumulation of neutrophils within the bronchoalveolar space. IL-17A may thereby also contribute to an increased local proteolytic burden. In the current study, we determined whether mRNA for IL-17A is elevated and protein expression of IL-17A occurs locally in inflammatory cells within the human bronchoalveolar space during severe inflammation caused by organic dust. We also assessed the expression of the elastinolytic protease MMP-9 in this airway compartment.METHODS: Six healthy, non-smoking human volunteers were exposed to organic dust in a swine confinement, a potent stimulus of neutrophil accumulation within the human bronchoalveolar space. Bronchoalveolar lavage (BAL) fluid was harvested 2 weeks before and 24 hours after the exposure and total and differential counts were conducted for inflammatory BAL cells. Messenger RNA for IL-17A was measured using reverse transcript polymerase chain reaction-enzyme linked immunoassay (RT-PCR-ELISA). Intracellular immunoreactivity (IR) for IL-17A and MMP-9, respectively, was determined in BAL cells.RESULTS: The exposure to organic dust caused more than a forty-fold increase of mRNA for IL-17A in BAL cells. IL-17A immunoreactivity was detected mainly in BAL lymphocytes, and the number of these IL-17A expressing lymphocytes displayed an eight-fold increase, even though not statistically significant. The increase in IL-17A mRNA was associated with a substantial increase of the number of BAL neutrophils expressing MMP-9 immunoreactivity.CONCLUSION: Exposure to organic dust increases local IL-17A mRNA and because there is intracellular expression in BAL lymphocytes, this suggests that IL-17A protein can originate from lymphocytes within the human bronchoalveolar space. The fact that the increased IL-17A mRNA is associated with an increased number of MMP-9-expressing neutrophils is compatible with IL-17A increasing the local proteolytic burden through its neutrophil-accumulating effect.
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| 6. |
- Ivanov, Stefan, 1974, et al.
(författare)
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Th-17 cells in the lungs?
- 2007
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Ingår i: Expert Rev Resp Med. ; 1:2, s. 279-293
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Lindén, Anders, 1961, et al.
(författare)
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Targeting IL-17 in the lungs
- 2010
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Ingår i: Book chapter for the volume "New drugs and targets for Asthma and COPD" edited by T. Hansel & P. Barnes, published by S. Karger AG, Basel 2010. - 9783805595667 ; , s. Ch 19; P 141-149
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 8. |
- Prause, Olof, 1973, et al.
(författare)
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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.
- 2009
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Ingår i: Pulmonary pharmacology & therapeutics. - : Elsevier BV. - 1094-5539. ; 22:3, s. 199-207
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-17 may play a critical role for the innate immune response in mammals. However, little is known about its production in T lymphocytes in comparison with other cells, in lung tissue and in the bronchoalveolar space in vivo. Even less is known about the effects of anti-inflammatory pharmacotherapy on this IL-17 production. In this study on mice we show that one single, intranasal exposure to endotoxin from Escherichia coli increases extracellular IL-17 protein in bronchoalveolar (BAL) samples during 3 days, and is accompanied by a local increase in neutrophils and other inflammatory cells. This endotoxin exposure also elevates IL-17 mRNA in lung tissue samples. Moreover, after endotoxin exposure, the absolute number of CD3-positive cells containing intracellular IL-17 protein is increased as well; from a moderate cell number in lung tissue samples and from virtually none in BAL samples; with the number in lung tissue exceeding that observed in BAL samples. Notably, we also demonstrate that among the cells that contain intracellular IL-17 protein after endotoxin exposure, the percentage of CD3-positive cells is similar to that of CD3-negative cells in lung tissue. In contrast, CD3-negative cells dominate among IL-17-containing cells in BAL samples. A high systemic dose of a glucocorticoid receptor agonist attenuates the endotoxin-induced increase in extracellular IL-17 protein in BAL samples, IL-17 mRNA in lung tissue samples, and in IL-17-containing CD3-positive cells in BAL and lung tissue samples. This is also true for the endotoxin-induced accumulation of neutrophils and other inflammatory BAL cells in vivo. A systemic dose of a calcineurin phosphatase inhibitor exerts a less complete and more selective effect on the endotoxin-induced increase in extracellular IL-17 protein and on neutrophils in BAL samples. In vitro, endotoxin also increases extracellular IL-17 protein in a co-culture of CD3-positive spleen cells and adherent mononuclear BAL cells; an increase that was inhibited by a glucocorticoid as well as by a calcineurin phosphatase inhibitor. In conclusion, endotoxin-induced IL-17 production and release from T lymphocytes originates from cells that reside in lung tissue and from cells that have been recruited to the bronchoalveolar space. In both compartments, there is also a substantial number of cells other than T lymphocytes that contain IL-17 after endotoxin exposure. The sustained IL-17 production from T lymphocytes and the associated neutrophil accumulation may be inhibited non-selectively through glucocorticoid receptor stimulation and more selectively through calcineurin phosphatase inhibition.
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| 9. |
- Sergejeva, Svetlana, 1972, et al.
(författare)
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Interleukin-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation
- 2005
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Ingår i: American journal of respiratory cell and molecular biology. - 1044-1549. ; 33:3, s. 248-53
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Tidskriftsartikel (refereegranskat)abstract
- Recent data indicate that the proinflammatory cytokine, interleukin (IL)-17, stimulates certain effector functions of human macrophages. We evaluated whether IL-17 mediates allergen-induced accumulation of airway macrophages and, if so, whether such an effect relates to the control of macrophage recruitment and survival. BALB/c mice were sensitized and challenged with ovalbumin. Three hours before challenge an anti-mouse IL-17 mAb (a-IL-17) was administered. Sampling was conducted 24 h after the allergen challenge. In vitro chemotaxis assay for blood monocytes and culture of airway macrophages, immunocytochemistry for Fas-antigen, and matrix metalloproteinase-9 (MMP-9) were used to determine the effect of IL-17 on the recruitment, survival, and activity of airway macrophages. A-IL-17 reduced the number of airway neutrophils and macrophages after allergen challenge. In vitro, recombinant IL-17 induced migration of blood monocytes and prolonged survival of airway macrophages. A-IL-17 also increased the expression of Fas-antigen in airway macrophages in vivo. Finally, the expression of MMP-9 by airway neutrophils and macrophages in vivo was downregulated by a-IL-17. This study indicates that endogenous IL-17 mediates the accumulation of macrophages during allergen-induced airway inflammation. IL-17 exerts its effects by acting directly on airway macrophages by promoting their recruitment and survival. Furthermore, IL-17 is involved in controlling the proteolytic activity of macrophages and neutrophils in allergen-induced airway inflammation.
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| 10. |
- Vlahos, Ross, et al.
(författare)
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Neutralizing granulocyte/macrophage colony-stimulating factor inhibits cigarette smoke-induced lung inflammation.
- 2010
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Ingår i: American journal of respiratory and critical care medicine. - 1535-4970. ; 182:1, s. 34-40
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Tidskriftsartikel (refereegranskat)abstract
- Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), and there is currently no satisfactory therapy to treat people with COPD. We have previously shown that granulocyte/macrophage colony-stimulating factor (GM-CSF) regulates lung innate immunity to LPS through Akt/Erk activation of nuclear factor-kappaB and activator protein (AP)-1.
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