Short CommunicationFree IL-18 and IL-33 cytokines in chronic spontaneous urticaria
Highlights
► In chronic spontaneous urticaria free IL-18 is increased. ► IL-18 binding protein counteracts the inflammatory effects of IL-18. ► IL-33 does not play a role in chronic spontaneous urticaria.
Introduction
Chronic spontaneous urticaria (CSU) is a common and disabling disease characterized by recurrent itchy wheals with or without angioedema for more than 6 weeks [1]. These symptoms are the consequence of skin mast cells degranulation with release of histamine and other vasoactive mediators. CSU is frequently characterized by autoreactivity as intradermal injection of autologous serum causes a wheal and flare reaction in 30–60% of patients [2]. Autoantibodies (anti-IgE, anti-FcεRI, anti-TPO) are detected in only one third of the cases, suggesting that other circulating mediators, including cytokines, may be involved in the pathophysiology of CSU.
Cytokines of the interleukin 1 (IL-1) family play a key role in mediating the activation of innate and acquired immune responses. A member of the IL-1 family is the pro-inflammatory cytokine IL-18, initially identified as a major inducer of IFN-γ in Th1 and NK cells, with a key role in Th1 activation in synergy with IL-12, although also capable of inducing Th2 cytokines [3]. IL-18 activity is regulated by IL-18BP, a soluble molecule that binds mature IL-18 with high affinity and prevents its interaction with cell surface receptors. In fact, IL-18 can be bound and neutralised by its soluble inhibitor IL-18BP and only the fraction of IL-18, that is not bound to IL-18BP, is actually free of interacting with the membrane receptors on target cells/organs and is biologically active. The interaction of IL-18 with IL-18BP has been described in detail, and is a stoichiometric 1:1 interaction with a Kd of 400 pM [4]. Thus, the level of free IL-18 depends on the absolute concentrations of both IL-18 and IL-18BP, and on their affinity of interaction, according to the law of mass action.
IL-33, constitutively expressed in endothelial and epithelial cells, is an intracellular protein that is also released in the extracellular space following cell injury. IL-33, similarly to IL-1α, may function both as a pro-inflammatory cytokine and as an intracellular nuclear factor involved in transcriptional regulation. Its receptor ST2 is an IL-1R-related protein expressed on Th2 cells, mast cells, basophils and eosinophils. Consistent with the expression of ST2, IL-33 induces or amplifies Th2-type responses, but also displays pro-inflammatory effects in different disease models [5]. A soluble form of ST2 (sST2) is generated by alternative gene splicing, which functions as a soluble decoy that binds IL-33 and prevents its binding to the membrane receptor [6].
The role of IL-33 in skin diseases is still unknown, but it has been shown that IL-33 mRNA levels are increased almost 10-fold in the skin of atopic dermatitis patients compared to healthy subjects [7]. Elevated levels of sST2 are associated to a wide range of diseases, from food allergy to Dengue virus infection to sepsis, and sST2 is being considered as a prognostic biomarker in heart failure [8].
In order to have a comprehensive view of the functional role of IL-18 and IL-33 in CSU, we evaluated the free IL-18 levels in sera of CSU patients, by analyzing IL-18 and IL-18BP concentrations, and measured the levels of IL-33 and its soluble receptor sST2. The results were correlated with the clinical features of the disease.
Section snippets
Subjects
We studied 73 CSU patients (46 female and 27 male; age 41 ± 16, range 14–89) and 40 sex-matched and age-matched healthy subjects (HS) (30 female and 10 male; age 50 ± 5, range 25–89) as control. CSU was diagnosed according to the EAACI/GA2LEN/EDF guidelines [1]. All the patients were being treated with non-sedating oral H1 anti-histamines, stopped 5 days before serum samples were taken for detection of Autologous Serum Skin Test (ASST), IL-18, IL-18BP, IL-33 and sST2. The study protocol conformed to
Results and discussion
Among the CSU patients, 32 (43.8%) had positive and 41 (56.2%) negative ASST. The levels of IL-18 and IL-18BP were significantly higher in CSU patients compared to HS (P < 0.0003 and P < 0.0001, respectively) (Fig. 1A and B), without differences between the ASST-positive (P < 0.0027 and P < 0.0021 for IL-18 and IL-18BP, respectively) and negative (P < 0.0013 and P < 0.0005 for IL-18 and IL-18BP, respectively) sub-groups. As shown in Fig. 1C, serum levels of free IL-18 were significantly higher in CSU
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