Short communicationAdministration of poly(I:C) improved dermatophagoides farinae-induced atopic dermatitis-like skin lesions in NC/Nga mice by the regulation of Th1/Th2 balance
Highlights
► Suppression of Df-induced AD-like skin lesions in NC/Nga mice model by poly(I:C). ► Poly(I:C) regulated the balance of Th1/Th2 cytokine production. ► Poly(I:C) might be a useful immunomodulatory agent for the treatment of human AD.
Introduction
Atopic dermatitis (AD) is chronically relapsing, non-contagious, and pruritic skin disorder with allergic inflammation [1], [2]. AD is caused by the complex interaction of genetic, pharmacological, environmental and psychological factors that result in the imbalance of immune system [3], [4]. Dysregulated T-helper 1 (Th1) and T-helper 2 (Th2) responses characterized by Th2-dominant allergic inflammation are thought to be central to the pathology of diseases such as AD and asthma [5], [6]. Particularly, Th2 immune responses mediated by interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13) are key to the pathogenesis of atopic disorders [7]. The presence of blood eosinophilia and increased serum IgE levels in the majority of patients with AD supports Th2 dominance in AD [8]. Some studies have demonstrated that interferon-gamma (IFN-γ), a Th1 cytokine, suppresses the production IgE by B cells, as well as the production of Th2 cytokine from Th2 cells [9], [10]. Therefore, it is important to consider the balance of Th1/Th2 cytokine in patients with immune diseases in allergic diseases such as AD.
NC/Nga mice spontaneously develop AD-like skin lesions under conventional condition, but not under specific pathogen-free (SPF) condition [11]. SPF NC/Nga mice treated with mite antigens develop clinical, immunological, and histological changes similar to those of AD patients, including an increase of number of mast cells and eosinophils degranulation, lymphocytes infiltration, as well as Th2 chemokines and their receptors [12], [13]. Additionally, the level of immunoglobulin (Ig) E in the serum increases gradually [14]. Recently, we have reported that the pathophysiological features of dermatitis induced by the repeated application with mite dermatophagoides farinae (Df) extract ointment in NC/Nga mice [15]. These findings suggest the possible involvement of Th2 cells in the development of AD in NC/Nga mice.
The immunopotentiator polyinosinic–polycytidylic acid [poly(I:C)], a synthetic analog of double-stranded RNA, leads to the activation of antigen presenting cells (APCs) such as B cells, dendritic cells (DCs), and macrophage through toll-like receptor (TLR) 3-mediated signaling [16]. Signaling through TLR3 leads to the secretion of proinflammatory of cytokine such as IL-12, IL-15, IL-18, and IFN-γ [17], [18], [19]. In addition, poly(I:C) has been used as an adjuvant in several pre-clinical studies for prevention vaccines [20], [21] and therapeutic cancer vaccines [22], [23]. Thus, poly(I:C) are being used as immunomodulatory agents because they could be able to shift Th1 responses from Th2 responses by activating the innate immune responses. Poly(I:C) have been shown to stimulate production of IL-12, IFN-γ in host cells [24], [25] and down-regulate Th2 responses in experimental animal models of allergic airway inflammation [26], [27]. Accordingly, it is conceivable that poly(I:C) could regulate the balance of Th1/Th2 cytokine production.
The goal of this study was to investigate the effects of poly(I:C) vaccine on changes of immune responses in the development of Df-induced dermatitis of NC/Nga mice, a condition histologically and clinically similar to human AD. The results showed that poly(I:C) vaccine improved the symptoms associated with dermatitis, reducing IgE, suppressing Th2-mediated cytokines and chemokines, at least in part, as a result of enhancement of IFN-γ-dominated Th1 responses.
Section snippets
Animals
Eight-week-old male NC/Nga mice were purchased from Shizuoka Laboratory Animal Center (Hamamatsu, Japan) for this study. The mice were maintained in uncontrolled conventional Laboratory Animal Facilities at the Dongguk University School of Medicine. The animal care and use committee of the research institute at Dongguk University Hospital approved all described studies.
Drugs and reagents
Poly(I:C) were purchased from Sigma–Aldrich Co. (γ-irradiated, St. Louis, MO, USA). Df body ointment was prepared by Biostir
In vitro effects of poly(I:C) on Df-induced AD-like skin lesions of NC/Nga mice
Df-induced NC/Nga mice are characterized by Th2-dominant response, and IgE production is mainly regulated by IL-5, IL-13, and IFN-γ released from Th cells [28]. To investigate the effect of poly(I:C) on the change of Th1 and Th2 immune responses in vitro, splenocytes isolated from Df-induced NC/Nga mice were cultured with poly(I:C) for 48 h. Treatment with poly(I:C) [10–50 μg] dose-dependently increased the production of IFN-γ (Fig. 1A). On the other hand, poly(I:C) [10–50 μg] dose-dependently
Discussion
As an immunologic aspect of AD, there are several reports that an altered Th1/Th2 balance owing to environmental factors are associated with various immune disorders [6], [30]. Therefore, any treatment that normalizes the Th1/Th2 balance can be useful for treatment of allergic disease such as AD. TLR stimulation, especially by TLR-9 ligand such as CpG-oligodeoxynucleotides (ODN), reduces Th-2 dependent allergic inflammation through induction of Th-1 responses and could prove useful in the
Acknowledgement
Conflicts of interest: None declared.
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