T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients

Stefano, Antonino Di; Caramori, Gaetano; Gnemmi, Isabella; Contoli, Marco; Vicari, C; Capelli, A; Magno, Francesca; D’Anna, Silvestro Ennio; Zanini, Andrea; Brun, Paola; Casolari, Paolo; Chung, Kian Fan; Barnes, Peter J.; Papi, Alberto; Adcock, Ian M.; Balbi, Bruno

doi:10.1111/j.1365-2249.2009.03965.x

Cited by 290 publications

(277 citation statements)

References 35 publications

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“…Expression of RORgT is a hallmark of Th17 development (8). Increased RORgT mRNA levels are associated with several human pathologies related to the presence of Th17-driven inflammatory processes (22,41). Our observations of USF-1-and USF-2-mediated RORgT expression in human lymphocytes raise the question of what role these transcription factors may play in Th17 development.…”

Section: Discussionmentioning

confidence: 76%

Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

Ratajewski

Walczak‐Drzewiecka

Sałkowska

et al. 2012

The Journal of Immunology

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Retinoic acid-related orphan receptor γT (RORγT) is the orphan nuclear receptor that regulates the development of Th17 cells and the expression of IL-17. The differentiation of Th17 cells is associated with the upregulation of RORγT mRNA, and the mechanisms regulating that process in human cells are not well understood. We investigated the transcriptional regulation of RORγT in a human lymphocytic cell line and Th17 differentiated from naive CD4+ cells from human peripheral blood. A series of experiments, including 5′ deletion and in situ mutagenesis analysis of the human RORγT promoter, chromatin immunoprecipitation, and overexpression of selected transcription factors, revealed that the transcription factors upstream stimulatory factor 1 (USF-1) and USF-2 are indispensable for the transcription of RORγT in human lymphocytes. There was also upregulation of USF-1 and USF-2 during the differentiation of Th17 cells from naive CD4+ cells. In this article, we report the first analysis, to our knowledge, of the human RORγT promoter and demonstrate the role of the USF-1 and USF-2 transcription factors in regulating the expression of RORγT in human lymphocytes. Thus, USFs are important for the molecular mechanisms of Th17 differentiation, and possible changes in the expression of USFs might be of interest for inflammatory conditions with a Th17 component. Furthermore, these observations suggest a possible link between metabolic disorders in which the role of glucose-induced USF expression has already been established and autoimmune diseases in which the upregulation of RORγT is frequently detected.

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Section: Discussionmentioning

confidence: 76%

Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

Ratajewski

Walczak‐Drzewiecka

Sałkowska

et al. 2012

The Journal of Immunology

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“…Although IL-17 has already been implicated in inflammatory lung disorders of humans [22][23][24][25][26], and IL-17 and/or IL-17 mRNA has been detected locally in these disorders, the presence of IL-17-containing memory Th cells has not previously been demonstrated in association with increased IL-17 production in the human lungs. The phenotype of the IL-17-containing T-cells demonstrated in the present study resembles what has previously been described for Th17 cells [7,10,27] with respect to these cells being CD4 + memory cells.…”

Section: Increase In Effector Molecules Downstream Of Il-17 and Il-22mentioning

confidence: 96%

Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin

Glader¹,

Smith²,

Malmhäll³

et al. 2010

European Respiratory Journal

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Previous studies on mouse models have indicated that interleukin (IL)-17 and IL-17-producing T-helper (Th) cells are important for pulmonary host defence against Gram-negative bacteria. Human correlates to these findings have not yet been demonstrated. The aim of the present study was to determine whether or not IL-17-producing Th cells are present and whether IL-17 and other Th17-associated cytokines are involved in the immunological response to endotoxin in human airways.Segmental exposure to endotoxin and contralateral exposure to vehicle were performed in the lungs of healthy volunteers, with subsequent bronchoalveolar lavage 12 or 24 h after exposure to study local changes in cytokines and inflammatory cells.Endotoxin exposure increased concentrations of IL-17, IL-22 and their downstream effector molecules, human b-defensin-2 and IL-8/CXC chemokine ligand 8, in bronchoalveolar lavage fluid. Th cells with the capacity to produce IL-17 were found among the bronchoalveolar lavage cells, and expression of IL-17 mRNA correlated with expression of the transcription factor, retinoic-acidreceptor-related orphan receptor C variant 2. Moreover, endotoxin increased the numbers of neutrophils, macrophages and IL-17-producing T-cells, as well as the concentration of the Th17-regulating cytokines, IL-21 and IL-23.In conclusion, IL-17-producing Th cells are present, and IL-17, as well as other Th17-associated cytokines, is involved in the immunological response to endotoxin in human airways.

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“…The role of IL-22 in the development of lung disease is not well understood (64,65). The expression of IL-22 as well as IL-17 is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients (64), suggesting that IL-22 plays some role in the airway inflammation.…”

Section: Discussionmentioning

confidence: 99%

High Expression of IL-22 Suppresses Antigen-Induced Immune Responses and Eosinophilic Airway Inflammation via an IL-10–Associated Mechanism

Nakagome

Imamura

Kawahata

et al. 2011

The Journal of Immunology

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Allergic inflammation in the airway is generally considered a Th2-type immune response. However, Th17-type immune responses also play important roles in this process, especially in the pathogenesis of severe asthma. IL-22 is a Th17-type cytokine and thus might play roles in the development of allergic airway inflammation. There is increasing evidence that IL-22 can act as a proinflammatory or anti-inflammatory cytokine depending on the inflammatory context. However, its role in Ag-induced immune responses is not well understood. This study examined whether IL-22 could suppress allergic airway inflammation and its mechanism of action. BALB/c mice were sensitized and challenged with OVA-Ag to induce airway inflammation. An IL-22–producing plasmid vector was delivered before the systemic sensitization or immediately before the airway challenge. Delivery of the IL-22 gene before sensitization, but not immediately before challenge, suppressed eosinophilic airway inflammation. IL-22 gene delivery suppressed Ag-induced proliferation and overall cytokine production in CD4+ T cells, indicating that it could suppress Ag-induced T cell priming. Antagonism of IL-22 by IL-22–binding protein abolished IL-22–induced immune suppression, suggesting that IL-22 protein itself played an essential role. IL-22 gene delivery neither increased regulatory T cells nor suppressed dendritic cell functions. The suppression by IL-22 was abolished by deletion of the IL-10 gene or neutralization of the IL-10 protein. Finally, IL-22 gene delivery increased IL-10 production in draining lymph nodes. These findings suggested that IL-22 could have an immunosuppressive effect during the early stage of an immune response. Furthermore, IL-10 plays an important role in the immune suppression by IL-22.

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T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients

Cited by 290 publications

References 35 publications

Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin

High Expression of IL-22 Suppresses Antigen-Induced Immune Responses and Eosinophilic Airway Inflammation via an IL-10–Associated Mechanism

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