| 1. |
- Andersson, Anders, et al.
(författare)
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Impact of tobacco smoke on interleukin-16 protein in human airways, lymphoid tissue and T lymphocytes
- 2004
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Ingår i: Clinical and experimental immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 138:1, s. 75-82
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Tidskriftsartikel (refereegranskat)abstract
- CD4(+) and CD8(+) lymphocytes are mobilized in severe chronic obstructive pulmonary disease (COPD) and the CD8(+) cytokine interleukin (IL)-16 is believed to be important in regulating the recruitment and activity of CD4(+) lymphocytes. In the current study, we examined whether tobacco smoke exerts an impact not only on IL-16 in the lower airways but also in CD4(+) or CD8(+) lymphocytes or in lymphoid tissue. The concentration of IL-16 protein was measured by enzyme-linked immunosorbent assay (ELISA) in concentrated bronchoalveolar lavage fluid (BALF) collected from 33 smokers with chronic bronchitis (CB), eight asymptomatic smokers (AS) and seven healthy never-smokers (NS). The concentrations of IL-16 and soluble IL-2 receptor alpha (sIL-2Ralpha) protein were also measured in conditioned medium from human blood CD4(+) and CD8(+) lymphocytes stimulated with tobacco smoke extract (TSE) in vitro. IL-16 mRNA was assessed in vitro as well, using reverse transcription-polymerase chain reaction (RT-PCR). Finally, the intracellular immunoreactivity for IL-16 protein (IL-16IR) was assessed in six matched pairs of palatine tonsils from smokers and non-smokers. BALF IL-16 was higher in CB and AS than in NS. TSE substantially increased the concentration of IL-16 but not sIL-2Ralpha in conditioned medium from CD4(+) and CD8(+) lymphocytes. There was no corresponding effect on IL-16 mRNA. IL-16IR in tonsils was lower in smokers than in non-smokers. The current findings demonstrate that tobacco smoke exerts a wide impact on the CD8(+) cytokine IL-16, in the airway lumen, in blood CD4(+) and CD8(+) lymphocytes and in lymphoid tissue. The effect on IL-16 release may be selective for preformed IL-16 in CD4(+) lymphocytes. New clinical studies are required to evaluate whether tobacco smoke mobilizes T lymphocytes via IL-16 in the lower airways and whether this mechanism can be targeted in COPD.
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| 2. |
- Hoshino, Hiroshi, et al.
(författare)
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Increased elastase and myeloperoxidase activity associated with neutrophil recruitment by IL-17 in airways in vivo
- 2000
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Ingår i: The Journal of allergy and clinical immunology. - 0091-6749. ; 105:1 Pt 1, s. 143-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A recent study demonstrated that intratracheal administration of the T-lymphocyte cytokine IL-17 recruits neutrophils into airways in vivo by C-X-C chemokine release. It is not known whether IL-17 may also activate airway neutrophils. OBJECTIVE: Our purpose was to evaluate whether IL-17 activates neutrophils in airways in vivo and, if so, whether the proinflammatory cytokine IL-1beta modulates this action of IL-17. METHODS: Intratracheal administration of human (h) IL-17 or rat (r) IL-1beta or hIL-17 plus rIL-1beta in anesthetized, spontaneously breathing rats was followed by bronchoalveolar lavage (BAL) 6 hours later. The BAL fluid was characterized in terms of neutrophil count, of the activity for myeloperoxidase (MPO), and in some cases of the activity for elastase (ELA). Isolated rat neutrophils were stimulated with hIL-17 in vitro, followed by characterization of MPO activity in the cell medium. RESULTS: hIL-17 (1 microg) increased the ELA and the MPO activity, as well as the neutrophil count in BAL fluid, whereas the proinflammatory cytokine rIL-1beta (2.5 ng) did not. Pretreatment with rIL-1beta enhanced IL-17induced ELA and MPO activity, without increasing the neutrophil count. The BAL ELA activity was inhibited by a specific inhibitor of neutrophil serine proteases. Stimulation with hIL-17 in vitro did not increase MPO activity in isolated neutrophils. CONCLUSION: IL-17 can activate neutrophils in association with their recruitment into the airways in vivo and this effect is probably achieved through induced release of mediators from other airway cells.
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| 3. |
- Laan, Martti, 1971, et al.
(författare)
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A role of GM-CSF in the accumulation of neutrophils in the airways caused by IL-17 and TNF-alpha
- 2003
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Ingår i: The European respiratory journal. - 0903-1936. ; 21:3, s. 387-93
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Tidskriftsartikel (refereegranskat)abstract
- The T-cell cytokine interleukin (IL)-17 selectively accumulates neutrophils in murine airways in vivo and may thus constitute a link between activation of T-lymphocytes and accumulation of neutrophils. In this study, the authors evaluated the role of granulocyte macrophage-colony stimulating factor (GM-CSF) in accumulation of neutrophils in the airways caused by IL-17 and tumour necrosis factor (TNF)-alpha. In vitro, human (h) IL-17 concentration-dependently stimulated the release of GM-CSF protein (enzyme-linked immunosorbent assay) in human bronchial epithelial cells (16HBE). IL-17 also time-dependently stimulated the release of GM-CSF protein in venous endothelial (human umbilical vein endothelial cells) cells in vitro. Co-stimulation with IL-17 plus the pro-inflammatory cytokine TNF-alpha potentiated the release of GM-CSF protein in 16HBE cells. hIL-17 also enhanced the expression of GM-CSF messenger ribonucleic acid in 16HBE cells (reverse transcriptase polymerase chain reaction), with a similar order of magnitude as TNF-alpha. Conditioned cell medium from bronchial epithelial cells co-stimulated with hIL-17 plus TNF-alpha prolonged survival (trypan blue exclusion) of human neutrophils in vitro and this effect was blocked by an anti-GM-CSF antibody. In vivo, local co-stimulation with mouse IL-17 plus TNF-alpha caused an additive potentiation of the accumulation of neutrophils in bronchoalveolar lavage fluid from mouse airways and this effect was blocked by an anti-GM-CSF antibody given systemically. In conclusion, granulocyte macrophage-colony stimulating factor is involved in the accumulation of neutrophils in the airways caused by interleukin-17 and tumour necrosis factor-alpha, probably via effects on both recruitment and survival of neutrophils.
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| 4. |
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| 5. |
- Laan, Martti, 1971, et al.
(författare)
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IL-16 in the airways of lung allograft recipients with acute rejection or obliterative bronchiolitis
- 2003
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Ingår i: Clin Exp Immunol. - 0009-9104. ; 133:2, s. 290-6
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Tidskriftsartikel (refereegranskat)abstract
- Acute rejection (AR) is the principal risk factor for obliterative bronchiolitis (OB), the major complication of lung transplantation. It is known that activated CD4+ T lymphocytes are involved in the development of AR and that interleukin (IL)-16 can inhibit the activity of CD4+ T lymphocytes. In this study, we evaluated whether the concentration of IL-16 in the airways is altered in AR or OB and, if so, how this IL-16 concentration relates to the number or activity of airway lymphocytes. The concentration of IL-16 protein was measured in bronchoalveolar lavage (BAL) fluid at three time-points in lung allograft recipients with either AR or OB and in matched controls using ELISA. The concentration of soluble IL-2 receptor (R) protein was measured in BAL fluid using ELISA as well, as an indicator of lymphocyte activity. The percentage of airway lymphocytes was evaluated by performing BAL differential cell counts. Lung allograft recipients with AR displayed lower IL-16 concentrations compared with matched control patients and this IL-16 concentration correlated negatively with the sIL-2R concentration, but it did not correlate with the percentage of lymphocytes in BAL fluid. In contrast, in BAL fluid from lung allograft recipients with OB, the IL-16 concentration was not altered compared with matched control patients and it did not correlate with the percentage of lymphocytes or with the sIL-2R concentration. These data are compatible with an increase in IL-16 playing a protective role against AR but not against OB and, hypothetically, this type of protective effect could be exerted via a down-regulation of the activity of T lymphocytes.
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| 6. |
- Laan, Martti, 1971, et al.
(författare)
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IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases
- 2001
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Ingår i: British journal of pharmacology. - 0007-1188. ; 133:1, s. 200-6
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Tidskriftsartikel (refereegranskat)abstract
- 1. Recent data indicate that interleukin (IL)-17 may contribute to neutrophilic airway inflammation by inducing the release of neutrophil-mobilizing cytokines from airway cells. The aim of this study was to evaluate the role of mitogen activated protein kinases in IL-17 induced release of IL-8 and IL-6 in bronchial epithelial cells. 2. Transformed human bronchial epithelial cells (16HBE) were stimulated with either IL-17 or vehicle. Both groups were treated either with SB202190 (inhibitor of p38 MAP kinase), PD98059 (inhibitor of extracellular-signal-regulated kinase [ERK] pathway), Ro-31-7549 (protein kinase C [PKC] inhibitor), LY 294002 (a phosphatidylinositol 3-kinase [PI 3-kinase] inhibitor) or vehicle. IL-6 and IL-8 levels were measured in conditioned media by ELISA. 3. The IL-17-induced release of IL-6 and IL-8 was concentration-dependently inhibited by SB202190 and by PD98059 in bronchial epithelial cells without affecting cell proliferation or survival. 4. Ro-31-7549 and LY294002 had no significant effect on IL-17-induced IL-6 or IL-8 release in bronchial epithelial cells. 4. Taken together, these data indicate a role for p38 and ERK kinase pathways in IL-17-induced release of neutrophil-mobilizing cytokines in human bronchial epithelial cells. These mechanisms constitute potential pharmacotherapeutical targets for inhibition of the IL-17-mediated airway neutrophilia.
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| 7. |
- Laan, Martti, 1971, et al.
(författare)
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Increased levels of interleukin-16 in the airways of tobacco smokers: relationship with peripheral blood T lymphocytes
- 1999
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Ingår i: Thorax. - 0040-6376. ; 54:10, s. 911-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The mechanisms behind the development of systemic immunomodulation among tobacco smokers are not fully understood, but several studies have indicated a role for CD8+ and/or CD4+ T cells. Interleukin (IL)-16, a cytokine released from inflammatory cells as well as bronchial epithelial cells, can recruit and activate CD4+ T cells. A study was undertaken to establish whether the IL-16 level is increased in the airways of tobacco smokers and to determine whether airway levels of IL-16 are related to the number and function of systemic T lymphocytes. METHODS: Bronchoalveolar lavage (BAL) fluid was collected from eight never smokers and 18 tobacco smokers without clinical airway symptoms, and from 16 tobacco smokers with clinical airway symptoms. Interleukin-16 protein levels in BAL fluid were determined using enzyme-linked immunosorbent assay (ELISA). Peripheral blood was collected for determination of CD4+ T cell content using flow cytometry. The responsiveness of systemic lymphocytes in smokers was assessed by measuring the proliferative response of peripheral blood lymphocytes to the superantigen staphylococcus enterotoxin A (SEA). RESULTS: The IL-16 protein level in the BAL fluid was significantly higher in tobacco smokers than in non-smokers. However, among tobacco smokers the IL-16 level was similar in asymptomatic smokers and in those with airway symptoms. The level of IL-16 in the BAL fluid of smokers correlated negatively with the percentage of CD4+ T cells and positively with superantigen stimulated lymphocyte proliferation in peripheral blood. CONCLUSIONS: In tobacco smokers the airway IL-16 level is increased and it is possible that this increase in IL-16 influences systemic immunomodulation by altering the number and responsiveness of systemic T lymphocytes.
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| 8. |
- Laan, Martti, 1971
(författare)
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Interleukin-17 in non-allergic airway inflammation
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 9. |
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| 10. |
- Laan, Martti, 1971, et al.
(författare)
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The IL-17 Family of Cytokines - Applications in Respiratory Medicine and Allergology.
- 2008
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Ingår i: Recent patents on inflammation & allergy drug discovery. - 1872-213X. ; 2:2, s. 82-91
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Tidskriftsartikel (refereegranskat)abstract
- The excessive accumulation of granulocytes is believed to constitute an important factor in inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD). Notably, T helper (Th) cells are known to produce cytokines that are involved in the mobilization of eosinophils and neutrophils. Currently, it is believed that a third population of Th cells, the recently described Th17 population, accounts for the production of several members of the interleukin (IL)-17 family of cytokines. The members of this cytokine family have proven abilities to recruit and activate neutrophils and eosiniphils. This review summarizes the evidence that these cytokines constitute key mediators of the Th-controlled granulocyte influx in airway disease and points out molecular target candidates for therapy as well as related patents.
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| 11. |
- Lindén, Anders, 1961, et al.
(författare)
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Airway neutrophils and interleukin-17
- 2000
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Ingår i: The European respiratory journal. - 0903-1936. ; 15:5, s. 973-7
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Tidskriftsartikel (refereegranskat)abstract
- It is well known that exacerbations of obstructive airways disease such as asthma and chronic obstructive pulmonary disease are associated with an increased number of neutrophils in the airways. However, the mechanisms behind this phenomenon are poorly understood. There is in vivo experimental evidence that the number of airway neutrophils is controlled by certain T-lymphocytes, but the mediators responsible for this lymphocyte-related neutrophilia have not yet been identified. In this review, novel evidence that the T-lymphocyte-related cytokine interleukin (IL)-17 can link the activation of certain T-lymphocytes to the recruitment and activation of airway neutrophils is described. The IL-17-induced neutrophil recruitment is mediated via induced CXC chemokine release through steroid-sensitive mechanisms and is modulated by release of endogenous tachykinins. These effects of IL-17 are potentiated by other pro-inflammatory cytokines such as (IL-1beta) and tumour necrosis factor-alpha. Clinical studies are needed to evaluate whether or not targeting these mechanisms can provide a useful pharmacotherapeutical approach against exaggerated mobilization of neutrophils in obstructive airways disease.
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| 12. |
- Lindén, Anders, 1961, et al.
(författare)
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Neutrophils, interleukin-17A and lung disease
- 2005
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Ingår i: The European respiratory journal. - 0903-1936. ; 25:1, s. 159-72
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Tidskriftsartikel (refereegranskat)abstract
- It is now established that an excessive and sustained mobilisation of neutrophils is a hallmark of several chronic inflammatory lung disorders, including severe obstructive lung disease. This article reviews evidence that the cytokine interleukin (IL)-17A is a major orchestrator of sustained neutrophilic mobilisation. Current evidence suggests that IL-17A is produced by T-lymphocytes, and that it exerts an orchestrating effect on the accumulation and associated activity of neutrophils in the bronchoalveolar space indirectly, through an induced release of specific cytokines and colony-stimulating factors in resident lung cells. Although the involvement of IL-17A in inflammatory lung disorders is supported by several recent studies, its causative role is still uncertain. However, the unique position of interleukin-17A at the interface between acquired and innate immunity puts this cytokine forward as an important signal for the reinforcement of host defence; it also implies that interleukin-17A may constitute a useful target for pharmacotherapeutic intervention.
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| 13. |
- Miyamoto, M., et al.
(författare)
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Endogenous IL-17 as a mediator of neutrophil recruitment caused by endotoxin exposure in mouse airways
- 2003
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Ingår i: Journal of immunology (Baltimore, Md.. - 0022-1767. ; 170:9, s. 4665-72
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Tidskriftsartikel (refereegranskat)abstract
- We have previously demonstrated that administration of the recently described cytokine IL-17 in rat airways in vivo recruits and activates neutrophils locally. In the current study, we examined whether endogenous IL-17 is involved in mediating neutrophil recruitment caused by endotoxin exposure in mouse airways. Our in vivo data show that local endotoxin exposure causes the release of free, soluble IL-17 protein 6 h later. Systemic pretreatment with a neutralizing anti-IL-17 Ab almost completely inhibits neutrophil recruitment 24 h, but not 6 h, after endotoxin exposure in the airways. Pretreatment with neutralizing anti-IL-6 and anti-macrophage inflammatory protein (MIP)-2 Abs inhibits neutrophil recruitment caused by local endotoxin exposure and IL-17, respectively. Our in vitro data show that endotoxin exposure stimulates the release of soluble IL-17 protein in T lymphocytes harvested from lung and spleen, respectively, and that this cytokine release requires coculture with airway macrophages. Intracellular IL-17 protein is detected in T lymphocytes from spleen but not in airway macrophages after coculture and stimulation of these two cell types. Finally, anti-IL-17 does not alter endotoxin-induced release of IL-6 and MIP-2 from T lymphocytes and airway macrophages in coculture. In conclusion, our results indicate that endotoxin exposure causes the release of IL-17 from T lymphocytes and that this cytokine release requires the presence of macrophages. Once released, endogenous IL-17 acts in part by inducing local release of neutrophil-mobilizing cytokines such as IL-6 and MIP-2, from nonlymphocyte, nonmacrophage cells, and this contributes to recruitment of neutrophils in the airways. These IL-17-related mechanisms constitute potential targets for pharmacotherapy against exaggerated neutrophil recruitment in airway disease.
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| 14. |
- Prause, Olof, 1973, et al.
(författare)
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Pharmacological modulation of interleukin-17-induced GCP-2-, GRO-alpha- and interleukin-8 release in human bronchial epithelial cells
- 2003
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Ingår i: European journal of pharmacology. - 0014-2999. ; 462:1-3, s. 193-8
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Tidskriftsartikel (refereegranskat)abstract
- The cytokine interleukin-17 may play a role in the recruitment of airway neutrophils, and interleukin-17 protein is increased in the airways of patients with asthma. In this study, we characterised the effect of interleukin-17 on the release of the neutrophil-recruiting cytokines granulocyte chemotactic protein (GCP)-2, growth-related oncogene (GRO)-alpha and interleukin-8 in human bronchial epithelial (HBE) cells. We also characterised the involvement of mitogen-activated protein (MAP) kinases as well as the effect of beta-adrenoceptor and glucocorticoid receptor stimulation and calcineurin and P-glycoprotein inhibition on these epithelial responses to interleukin-17. We found that interleukin-17 (1-1000 ng/ml) increased the release of GCP-2, GRO-alpha and interleukin-8 in a concentration-dependent manner. This interleukin-17-induced release of C-X-C chemokines was sensitive to inhibition of the p38 MAP kinase pathway and to stimulation of glucocorticoid receptors. In contrast, stimulation of beta-adrenoceptors increased the release of interleukin-8 and did not markedly alter the release of GCP-2 and GRO-alpha. Inhibition of calcineurin and of P-glycoproteins did not exert any substantial effect on the release of C-X-C chemokines. In conclusion, interleukin-17 bears the potential to increase neutrophil recruitment into the airways by releasing several, different C-X-C chemokines, including GCP-2, GRO-alpha and interleukin-8 in human bronchial epithelial cells. Inhibition of the p38 MAP kinase pathway and glucocorticoid receptor stimulation constitute two credible therapeutic strategies against this interleukin-17-induced release of neutrophil-recruiting cytokines.
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