Thymic stromal lymphopoietin: a new cytokine in asthma

https://doi.org/10.1016/j.coph.2008.03.002Get rights and content

Airway epithelial cells provide mechanical and immune protection against pathogens and allergens. Following activation, these cells produce a wide range of cytokines including thymic stromal lymphopoietin (TSLP). Recently it was established that a high level of TSLP is associated with asthma in mice and in humans. These findings suggest that interfering with the ability of cells to respond to TSLP might prevent the development of airway inflammation. Our review presents current knowledge on mediators that induce TSLP production and on the actions of TSLP on different populations of cells that are related to airway inflammation. TSLP affects dendritic cells, T cells, NKT cells, and mast cells, indicative of the broad role of TSLP in the regulation of inflammatory/allergic processes.

Introduction

Asthma is a disease characterized by chronic airway inflammation that is mediated by T-helper 2 (TH2) cells [1, 2]. TH2 cells release interleukin-4 (IL-4), IL-5, IL-9, and IL-13, driving IgE production by B cells, stimulating basophils and eosinophils, enhancing mast cell differentiation, and increasing mucus production [1, 2]. Allergens trigger the crosslinking of IgE on mast cells, leading to the activation and degranulation of these cells. The inflammatory mediators released by mast cells cause bronchial smooth muscle contraction, vascular permeability, inflammatory cell infiltrate, increased mucus in airways, epithelial cell loss, and goblet cell hyperplasia [1, 3].

Airway epithelial cells provide the initial barrier against pathogens (allergens) invading the lung. In addition to mechanical protection, epithelial cells provide immune defense against harmful materials. Following their activation, these cells produce an array of cytokines and chemokines, including IL-1, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon α and interferon β, tumor necrosis factor-α (TNF-α), and RANTES (regulated upon activation, normal T cell expressed and secreted cytokine), eotaxin and others, which promote the recruitment and activation of immune and inflammatory cells [4, 5, 6]. Among the mediators produced by epithelial cells is thymic stromal lymphopoietin (TSLP) [7]. Recent studies have established that high levels of TSLP are associated with airway inflammatory disease in humans and mice [8•, 9•]. Strikingly, mice lacking TSLPR fail to develop inflammatory allergic response in the lung [10••]. Conversely, the overexpression of TSLP in transgenic mice induces spontaneous airway inflammation and atopic dermatitis, consistent with an important role for this cytokine in allergy/inflammation [11••, 12].

Section snippets

TSLP/TSLPR signaling

TSLP was originally identified as a growth factor in the supernatant of Z210R.1 thymic stromal cells that support proliferation and survival of the NAG8/7 pre-B cell line [13]. TSLP is a short-chain four α-helical bundle type I cytokine that is closely related to interleukin-7 (IL-7), another stromal factor [14, 15]. IL-7 signals via IL-7Rα and the common cytokine receptor γ chain (γc), a protein that is also a critical component of the receptors for IL-2, IL-4, IL-9, IL-15, and IL-21 [16].

Induction of TSLP in allergic disorders

Studies on TSLP have indicated that epithelial cells, keratinocytes, and stromal cells are major producers of TSLP [7]. Recently, it was demonstrated that allergen-activated basophils also produce TSLP and thus also may be important in the initiation of TH2 responses [21]. TSLP is implicated in allergic inflammation, and a number of mediators have been defined, with the potential to promote TSLP expression that might be associated with airway inflammation and atopic dermatitis (Figure 2) [22,

The role of TSLP in the development of immune cells

TSLP, like IL-7, has effects in T-cell and B-cell lymphopoiesis [9•, 29, 30, 33]. In mice, disruption of IL-7Rα signaling leads to T-cell and B-cell lymphopenia and an absence of γδ T cells [31]. In humans, mutation of the IL7R gene results in a form of severe combined immunodeficiency in which T cells are profoundly diminished in number while other lineages are intact [31, 32]. It is reasonable to predict that TSLP might partially replace the role of IL-7 in T-cell development because IL-7Rα

TSLP exerts actions on multiple lineages

TSLP has effects on a range of immune cells, including dendritic cells (DCs), T cells, natural killer T (NKT) cells, and mast cells. These effects will be summarized, focusing on the relationship to asthma (Figure 2).

Old and new therapeutic strategies

The general approach in the treatment of asthma is to diminish symptoms by using bronchodilators and corticosteroids that can prevent and reduce airway swelling and decrease the amount of mucus in the lungs [1]. However, these medications can have side effects, and tolerance can arise during long-term treatment. Moreover, because each case of asthma is different, treatment needs to be modified for each person. A novel approach for asthma is to develop immunological therapies to prevent its

Conclusion

TSLP is a cytokine of tremendous interest that is implicated as playing a pathophysiologic role in allergic inflammatory disease, including asthma and atopic skin disease. As such, it is a potential target for the modulation of inflammation/allergy. Although highly related to IL-7, including the sharing of a receptor component, TSLP is distinctive in having a greater role in inflammation whereas IL-7 appears to be more important for lymphoid development and survival. Additional data on the

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (49)

  • S.D. Message et al.

    Host defense function of the airway epithelium in health and disease: clinical background

    J Leukoc Biol

    (2004)
  • V. Soumelis et al.

    Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP

    Nat Immunol

    (2002)
  • S. Ying et al.

    Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity

    J Immunol

    (2005)
  • Y.J. Liu et al.

    TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation

    Annu Rev Immunol

    (2007)
  • A. Al-Shami et al.

    A role for TSLP in the development of inflammation in an asthma model

    J Exp Med

    (2005)
  • B. Zhou et al.

    Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice

    Nat Immunol

    (2005)
  • J. Yoo et al.

    Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin

    J Exp Med

    (2005)
  • S.L. Friend et al.

    A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells

    Exp Hematol

    (1994)
  • J.E. Sims et al.

    Molecular cloning and biological characterization of a novel murine lymphoid growth factor

    J Exp Med

    (2000)
  • H. Quentmeier et al.

    Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation

    Leukemia

    (2001)
  • W.J. Leonard

    Cytokines and immunodeficiency diseases

    Nat Rev Immunol

    (2001)
  • L.S. Park et al.

    Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor

    J Exp Med

    (2000)
  • A. Pandey et al.

    Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin

    Nat Immunol

    (2000)
  • D.E. Isaksen et al.

    Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction

    J Immunol

    (1999)
  • Cited by (61)

    • Interleukin 7 receptor is required for myeloid cell homeostasis and reconstitution by hematopoietic stem cells

      2020, Experimental Hematology
      Citation Excerpt :

      Conversely, when we transplanted WT HSCs into an IL7R null background, we observed that the donor chimerism of eosinophils and neutrophils in the lungs was significantly impaired (Figure 3D), but that circulating “traditional” myeloid cells were efficiently generated (Supplementary Figure E2B). Interestingly, it has been reported that eosinophil homeostasis relies on lymphocyte- and stroma-secreted survival factors [26,27,30–33]. We found that two known eosinophil regulators, eotaxin and IL-5, were reduced in the IL7Rα−/− mice.

    • Immunological axis of berberine in managing inflammation underlying chronic respiratory inflammatory diseases

      2020, Chemico-Biological Interactions
      Citation Excerpt :

      Hence, the anti-inflammatory properties of berberine presents a potential case in the treatment of COPD. High levels of TSLP expressions have been detected in asthmatic airways in human and animal models, and researchers suggest that suppression of TSLP will be a positive approach to modulate allergic inflammatory diseases including asthma [32–37]. Berberine has shown to suppress TSLP expression effectively.

    • Mutagenic players in ALL progression and their associated signaling pathways

      2019, Cancer Genetics
      Citation Excerpt :

      CRLF2 also known as thymic stromal lymphopoietin receptor (TSLPR) belongs to type I cytokine receptor family. Its ligand thymic stromal lymphopoietin (TSLP) is an epithelial derived cytokine that activates dendritic cells, regulates proliferation and survival of precursor B-cells but gets downregulated in mature B-cells [68]. As cytokine receptors lack intrinsic catalytic activity so they are dependent on tyrosine kinase (Janus kinase) for their activity.

    • Leveraging genomics to uncover the genetic, environmental and age-related factors leading to asthma

      2019, Genomic and Precision Medicine: Infectious and Inflammatory Disease
    View all citing articles on Scopus
    View full text