Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma.

Laboratory for Respiratory Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research, Kanagawa, Japan.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 4.11). 06/2011; 44(6):787-93. DOI: 10.1165/rcmb.2009-0418OC
Source: PubMed

ABSTRACT Thymic stromal lymphopoietin (TSLP) triggers dendritic cell--mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)-1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter--reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting β(2)-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14-1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Thymic stromal lymphopoietin (TSLP) controls allergic T(H)2 inflammatory responses through induction of distinct activation programs in dendritic cells (DCs). However, knowledge about TSLP receptor expression and functional consequences of receptor activation by DCs residing in the human respiratory tract is limited. Objective: We wanted to identify TSLP-responding DC populations in the human upper airway mucosa and assess the TSLP-mediated effects on such DCs in allergic airway responses. Results: We found that the TSLP receptor was constitutively and preferentially expressed by myeloid CD1c(+) DCs in the human airway mucosa and that the density of this DC subset in nasal mucosa increased significantly after in vivo allergen challenge of patients with allergic rhinitis. In vitro, TSLP strongly enhanced the capacity of CD1c(+) DCs to activate allergen-specific memory CD4(+) T cells. Moreover, TSLP rapidly induced CCR7 expression on CD1c(+) DCs. However, T(H)2 cytokines attenuated TSLP-mediated CCR7 induction, thus inhibiting the TSLP-induced DC migration potential to the draining lymph nodes. Conclusion: Our results suggest that TSLP-mediated activation of human nasal mucosal CD1c(+) DCs triggers CCR7-dependent migration to the draining lymph nodes and enhances their capacity to initiate T(H)2 responses. However, the observation that T(H)2 cytokines abrogate the induction of CCR7 implies that during a T(H)2-mediated inflammatory reaction, TLSP-activated CD1c(+) DCs are retained in the inflamed tissue to further exacerbate local inflammation by activating local antigen-specific memory T(H)2 cells.
    Journal of Allergy and Clinical Immunology 06/2014; 134(3). DOI:10.1016/j.jaci.2014.05.010 · 11.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Epithelial cell-derived mediators have emerged as key players for instigating local remodeling and the associated cellular inflammation in asthmatic airways. In particular, the epithelial-derived cytokine, thymic stromal lymphopoietin (TSLP), has been identified as a master switch for allergic inflammation. Areas covered: TSLP is expressed by structural and immune cells at the site of allergen entry in the airways. Stimuli for release of TSLP include common triggers of asthma symptoms, and TSLP levels correlate with disease severity. TSLP regulates helper T cell 2 (Th2) humoral immunity through upregulating OX40L on dendritic cells (DCs), which drives Th2 lymphocytes; however, activation of several other cells by TSLP also supports the development of Th2 inflammation. Animal models of asthma demonstrate that increased levels of TSLP can induce many of the characteristics of asthma. Expert opinion: The work conducted to date supports a critical role of TSLP in the pathogenesis of allergic asthma. The first clinical trial to block the downstream effects of OX40L has shown reduced levels of circulating IgE and airway eosinophils, confirming the importance of TSLP-induced OX40L levels on DCs. Clinical trials with TSLP blockade are underway and will unequivocally confirm whether TSLP is indeed a key driver of allergic inflammation in asthma.
    Expert Opinion on Therapeutic Targets 07/2014; 18(7):771-85. DOI:10.1517/14728222.2014.915314 · 4.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Thymic stromal lymphopoietin (TSLP) is a key factor in the development of allergic asthma. Numbers of TH2 memory cells gradually increase in allergic patients with the progression of disease and persist in the lungs during remission, although the mechanism is not clear. We sought to define the role of TSLP in TH2 memory cell generation and maintenance in vivo. Adoptive transfer of wild-type and thymic stromal lymphopoietin receptor (TSLPR)-deficient ovalbumin-specific CD4(+) T cells before TH2 sensitization was used to define T cell-specific TSLP effects. Atopic dermatitis and increased serum TSLP concentrations were induced by topical application of the vitamin D3 analog MC903. Memory cells in peripheral blood were monitored weekly with flow cytometry. Memory recall was tested after intranasal ovalbumin challenge. TSLP signaling in CD4(+) T cells is required for the generation/maintenance of memory cells after in vivo priming. TSLPR-deficient CD4(+) T cells have no defects in proliferation but do not survive 1 week after sensitization, and increased TSLP expression during sensitization significantly increased the frequency of memory cells. Although in vitro-differentiated TSLPR-deficient TH2 cells develop into memory cells with equal efficiency to wild-type cells, the recall response to airway antigen challenge is impaired. Moreover, after antigen challenge of mice with established TH2 memory, TSLP signaling in CD4(+) T cells significantly affects memory cell generation/maintenance from secondary effector cells. TSLP signaling in CD4(+) T cells is required for not only TH2 memory cell formation in vivo but also the recall response of the memory cells to local antigen challenge. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 10/2014; DOI:10.1016/j.jaci.2014.09.015 · 11.25 Impact Factor