IL-33 and Thymic Stromal Lymphopoietin in mast cell functions.

Thymic Stromal Lymphopoietin (TSLP) and Interleukin 33 (IL-33) are two cytokines released by cells that are in proximity to our environment, e.g., keratinocytes of the skin and epithelial cells of the airways. Pathogens, allergens, chemicals and other agents induce the release of TSLP and IL-33, which are recognized by mast cells. TSLP and IL-33 affect several mast cell functions, including growth, survival and mediator release. These molecules do not directly induce exocytosis, but cause release of de novo synthesized lipid mediators and cytokines. TSLP and IL-33 are also implicated in inflammatory diseases where mast cells are known to be an important part of the pathogenesis, e.g., asthma and atopic dermatitis. In this chapter we describe and discuss the implications of TSLP and IL-33 on mast cell functions in health and disease.

Vaccination against IL-33 Inhibits Airway Hyperresponsiveness and Inflammation in a House Dust Mite Model of Asthma.

In several clinical and experimental studies IL-33 and its receptor have been found to play important roles in the development of asthma and allergic airway inflammation. We evaluated the effects of vaccination against IL-33 in a mouse model of airway inflammation induced by house dust mite (HDM) allergen. Balb/c mice received the IL-33 vaccine subcutaneously, followed by intranasal administration of HDM for up to six weeks. Vaccination against IL-33 induced high titers of specific anti-IL-33 IgG antibodies that inhibited HDM-induced airway hyperresponsiveness (AHR) in the conducting airways and tissue damping. The vaccination also attenuated the HDM-induced elevation in the numbers of eosinophils in bronchoalveolar lavage fluid (BALF) and suppressed the accumulation of inflammatory cells in the airways. Furthermore, the levels of IL-17A, IL-25, IL-33 and TSLP in lung tissue homogenates were reduced by vaccination against IL-33. These observations demonstrate that vaccination against IL-33 inhibits HDM-induced development of AHR, airway inflammation and production of inflammatory cytokines. The results also indicate an important role of IL-33 in the regulation of AHR of the distal lung compartments. Thus, administration of such a vaccine is potentially an effective therapeutic tool for treating allergic asthma.

Experimentally induced psoriatic lesions associate with rapid but transient decrease in interleukin-33 immunostaining in epidermis.

A slight epidermal damage can induce the Köbner reaction in psoriasis, and the "alarmin", interleukin-33 (IL-33), may be involved in this process. Therefore, the uninvolved psoriatic skin was tape-stripped, and skin biopsies were collected at 0 day, 2 h and 3 days or at 0 day, 1 day and 7 days for immunohistochemistry. Eight patients out of 18 with the positive Köbner reaction showed a decrease in epidermal thickness and revealed transient reduction in epidermal nuclear immunostaining of IL-33 in 2-h, 1-day, 3-day biopsies compared to the 10 Köbner-negative patients. In keratinocyte cultures, the full-length 32-kDa IL-33 was detected after damaging the cells with freeze-thawing. Interestingly, a very low concentration of rh-IL-33 (0.001­0.01 ng/ml) significantly stimulated (3)H-thymidine uptake by human LAD2 mast cells, but not by psoriatic peripheral blood mononuclear cells. The results show that epidermal IL-33 associates with positive Köbner response, and only a small amount of the IL-33 apparently released may induce proliferation in dermal mast cells.