Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin (original) (raw)
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Journal of immunology (Baltimore, Md. : 1950), 2003
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 airwa...
Contribution of IL-17 to the pulmonary inflammatory response
Th 17 Cells: Role in Inflammation and Autoimmune Disease, 2009
ABSTRACT Airway exposure to endotoxin and other microbial Toll-like receptor (TLR) agonists induces a rapid production of mediators including IL-1, neutrophil recruitment and bronchoconstriction, which are abrogated in mice deficient for distinct TLRs or the common adaptor molecule myeloid differentiation factor 88 (MyD88). Intranasal IL-17 administration causes acute neutrophilic lung inflammation in a proinflammatory environment. Recent investigations revealed that IL-17 is up-regulated upon endotoxin aerosol exposure and neutralization of IL-17 diminished endotoxininduced inflammation, suggesting a role of endogenous IL-17 in endotoxin-induced lung inflammation. Furthermore, administration of IL-1β mobilizes neutrophils and induces IL-17 production in the lung. Therefore, IL-17 might participates in IL-1β-induced lung inflammation. Importantly, lung injury leads to NALP3 inflammasome activation, leading to IL-1β-dependent acute inflammation. The participation of IL-17 in this response is discussed. In conclusion, TLR-agonist and injury-induced lung inflammation depend in part on IL-1β and IL-17. The role of inflammasome activation cleaving pro-IL-1β leading to mature IL-1ß and IL-1β-dependent IL-17 production and inflammation need to be explored further.
Modulation of bronchial epithelial cells by IL-17
Journal of Allergy and Clinical Immunology, 2001
Background: The induction of epithelial cytokines/chemokines is crucial in the migration of leukocytes, and its regulatory mechanisms remain incompletely defined. Objective: To determine the role of IL-17, a CD4 + T cell-derived cytokine, in modulation of primary bronchial epithelial cells, the expression of IL-6, IL-8, and intercellular adhesion molecule 1 (ICAM-1) and the potential involvement of mitogen-activated protein (MAP) kinases in IL-17-mediated signaling were examined. Methods: The levels of gene expression and protein production for IL-6 and IL-8 in IL-17-treated cells, in the presence or absence of MAP kinase inhibitors, were analyzed by RT-PCR and ELISA, respectively, and activation of MAP kinases was determined by Western blot analyses. Results: We showed first that IL-17 induced time-dependent expression of IL-6 and IL-8 but not of the chemokines eotaxin and RANTES. In addition, IL-17 induced activation of extracellular signal-regulated kinase 1/2 but not of p38 or JNK kinases. A selective MAP kinase kinase inhibitor, PD98059, inhibited IL-17-induced IL-6 and IL-8. A combination of IL-17 and each of the cytokines IL-4, IL-13, and IFN-γ further enhanced IL-8 expression. IL-17 alone did not induce ICAM-1 expression and showed no effect on IL-4-or IL-13-induced ICAM-1 expression. In contrast, a combination of IL-17 and IFN-γ augmented IL-6 and ICAM-1 expression. Conclusion: These findings suggest that IL-17, alone or in combination with other cytokines, modulates airway inflammation via-in part-the expression of epithelial IL-6, IL-8, and ICAM-1. (
Free, soluble interleukin-17 protein during severe inflammation in human airways
European Respiratory Journal, 2002
Free, soluble interleukin-17 protein during severe inflammation in human airways. M. Laan, L. Palmberg, K. Larsson, A. Lindén. #ERS Journals Ltd 2002. ABSTRACT: Studies in rodents indicate that the cytokine, interleukin (IL)-17, links the activation of T-lymphocytes to neutrophilic inflammation. The aim of the current study was to determine whether free, soluble IL-17 protein can be released during severe inflammation in human airways.
Interleukin-17F Induces Pulmonary Neutrophilia and Amplifies Antigen-induced Allergic Response
American Journal of Respiratory and Critical Care Medicine, 2005
Interleukin (IL)-17F is a recently described human cytokine belonging to the IL-17 gene family, but its in vivo function remains to be determined. To this end, a full-length mouse IL-17F cDNA sequence with a 483-bp coding region sequence was first identified. Pulmonary gene transfer of an IL-17F expression construct (pcDNAmIL-17F) in mice was used to investigate its regulatory role. The results showed first that a significant increase in the number of neutrophils was seen in the bronchoalveolar lavage fluids of IL-17F-transduced mice, concomitant with increased expression of genes encoding C-X-C chemokines and inflammatory cytokines when compared with mock and phosphate-buffered saline control animals. Mucosal transfer of the IL-17F gene in ovalbumin (OVA)-sensitized mice before antigen (Ag) challenge enhanced the levels of Ag-induced pulmonary neutrophilia, but not eosinophilia, goblet cell hyperplasia, and mucin gene expression. However, no significant change in the levels of Th2 cytokine expression was noted. A significant enhancement of ventilatory timing in response to inhaled methacholine was also seen in IL-17F-transduced, Ag-sensitized mice, whereas a small but significant increase was found in IL-17F-transduced, naive mice. These results suggest a role for IL-17F in the induction of neutrophilia in the lungs and in the exacerbation of Ag-induced pulmonary inflammation.
IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines
Journal of allergy and …, 2001
Background: IL-17 is a cytokine that has been reported to be produced by T lymphocytes. In vitro, IL-17 activates fibroblasts and macrophages for the secretion of GM-CSF, TNF-α, IL-1β, and IL-6. A number of these cytokines are involved in the airway remodeling that is observed within the lungs of asthmatic individuals. Objective: In this study, we investigated the expression of IL-17 in sputum and bronchoalveolar lavage specimens obtained from asthmatic subjects and from nonasthmatic control subjects. Methods: IL-17 was detected through use of immunocytochemistry, in situ hybridization, and Western blot. Bronchial fibroblasts were stimulated with IL-17, and cytokine production and chemokine production were detected through use of ELISA and RT-PCR. Results: Using immunocytochemistry, we demonstrated that the numbers of cells positive for IL-17 are significantly increased in sputum and bronchoalveolar lavage fluids of subjects with asthma in comparison with control subjects (P < .001 and P < .005, respectively). We demonstrated that in addition to T cells, eosinophils in sputum and bronchoalveolar lavage fluids expressed IL-17. Peripheral blood eosinophils were also positive for IL-17, and the level of IL-17 in eosinophils purified from peripheral blood was significantly higher in subjects with asthma than in controls (P < .01). To further investigate the mechanism of action of IL-17 in vivo, we examined the effect of this cytokine on fibroblasts isolated from bronchial biopsies of asthmatic and nonasthmatic subjects. IL-17 did enhance the production of profibrotic cytokines (IL-6 and IL-11) by fibroblasts, and this was inhibited by dexamethasone. Similarly, IL-17 increased the level of other fibroblast-derived inflammatory mediators, such as the α-chemokines, IL-8, and growth-related oncogene-α. Conclusion: Our results, which demonstrate for the first time that eosinophils are a potential source of IL-17 within asth-matic airways, suggest that IL-17 might have the potential to amplify inflammatory responses through the release of proinflammatory mediators such as α-chemokines. (J Allergy Clin Immunol 2001;108:430-8.)
T cell subsets in human airways prior to and following endobronchial administration of endotoxin
Respirology (Carlton, Vic.), 2015
Bronchial instillation of lipopolysaccharide (LPS) provides a reversible model of lung inflammation that may resemble early stages of acute respiratory distress syndrome (ARDS). We investigated the distributions of T-cell subsets in the human airways and sought to determine whether pro- and anti-inflammatory T cells are involved in the local immune response to lung inflammation. Bronchoalveolar lavage (BAL) was performed in 15 healthy volunteers, after which Escherichia coli LPS (4 ng/kg) was administered. BAL was repeated at 2, 4, 6, 8 or 24 h after instillation of LPS. BALF CD4+ and CD8+ T cells were characterized by expression of activation markers (HLA-DR+CD38+), the proportion of cells expressing naïve markers (CD45RA+CD27+CCR7+) was lower, and that of cells expressing effector memory markers (CD45RA-CD27+CCR7-) was higher, compared with peripheral blood. Bronchial LPS induced a local inflammatory response with recruitment of CD4+ (P = 0.014), CD8+ T cells (P = 0.034), an incre...
Interleukin-17 and airway remodelling
Pulmonary Pharmacology & Therapeutics, 2006
Interleukin (IL)-17A is emerging as important in reinforcing innate immunity by orchestrating sustained neutrophilic mobilisation. Even though there are indications of association with specific airway diseases, there is still no final proof that IL-17A plays a truly causative pathogenic role. There is evidence in mice that endogenous IL-17A contributes to the development of allergen-induced airway hyperresponsiveness and there is also evidence that IL-17A stimulates the release of several cytokines with known capacity for airway remodelling, from cells normally residing in the airways. New studies are required to determine whether these effects on local cells actually contribute to airway remodelling in vivo. If this is the case, then IL-17A may constitute a useful target for pharmacotherapeutic intervention in allergic airway disease.