Thymic stromal lymphopoietin: a new cytokine in asthma
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
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