**1. Introduction**

38 Atopic Dermatitis – Disease Etiology and Clinical Management

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Arimura, A. (2007). Impact of T-cell receptor Vbeta haplotypes on the development of dermatitis in DS-Nh mice: synergistic production of interleukin-13 caused by staphylococcal enterotoxin C and peptide glycans from *Staphylococcus aureus*. Atopic dermatitis (AD) is a chronic, relapsing, highly pruritic inflammatory skin disease (1, 2). Analyses of the cytokine expression profile in skin lesions of AD patients show that the Th2-type immune response is dominant in AD inflammation (3, 4). Interleukin-4 (IL-4), IL-5, and IL-13 are signature cytokines of the Th2-type immune response. Expression of IL-4 and IL-13 is significantly high in acute lesions of AD skin; however, it is downregulated in chronic lesions. In contrast, expression of IL-5 is more elevated in chronic lesions than in acute lesions. High expression of IL-4, IL-5, and IL-13 in AD skins leads to high serum levels of IgE and eosinophilia, typical clinical features of AD. In addition to IL-5, expression of interferon-γ (IFN-γ) and IL-12 is elevated in chronic skin lesions of AD. IFN-γ and IL-12 are signature cytokines of Th1-type immune response. It has remained unclear why this immune milieu change occurs.

Based on observations of the predominant Th2-type immune responses in AD patients, many studies using model mice or involving genetic association have been performed to investigate the role played by Th2-type cytokines in the pathogenesis of AD. It is hoped that Th2-type cytokines will prove to be good targets to develop therapeutic agents for AD. In this chapter, we focus on these topics; we do not review the details of the structures, the signal pathways, or the biological functions of these Th2-type cytokines. Please refer to other articles regarding with these subjects (5-10).

#### **2. Th2-type cytokines in model mice**

Animal models are useful to understand the pathogenesis of AD and to develop therapeutic agents for AD. Among various species, mouse models have been primarily used, because genetically manipulated mice are available. Mouse models of AD can be categorized into three groups (2): (1) mice that spontaneously develop AD-like skin lesions, (2) mice epicutaneously sensitized with allergens, and (3) genetically engineered mice. It has been reported that several AD model mice that spontaneously develop AD-like skin lesions such as Nc/Nga mice (11) and DS-Nh mice (12) show a Th2-type–dominant immune milieu, suggesting that Th2-type cytokines are involved in pathogenesis in these mice. However, the situation is more complex, because it has been demonstrated that Nc/Nga mice deficient

The Roles of Th2-Type Cytokines in the Pathogenesis of Atopic Dermatitis 41

Geha's group established AD model mice by repeated epicutaneous sensitization to OVA (14). These mice manifest AD-like skin lesions including acanthosis, spongiosis, and infiltration of neutrophils, lymphocytes, mast cells, and eosinophils into the dermis. Expression of Th2-type (IL-4, IL-5 and IL-13) cytokines is up-regulated with little or no change of IFN-γ expression (2, 14). Furthermore, serum levels of total or OVA-specific IgE and IgG1 are elevated. This mouse model has been used to investigate involvement of

The role of IL-4 in OVA-sensitized AD model mice is complex (15). The eosinophil numbers decrease in the dermis of OVA-sensitized IL-4–deficient mice showing an important role of IL-4 for infiltration of eosinophils. However, the numbers of CD45+, CD3+, CD4+, and CD8+ cells and expression of MIP-2, MIP-1β, IP-10, and RANTES increase compared to wild type mice, suggesting that IL-4 has an inhibitory role in expression of chemokines to recruit T cells. It is of note that thickness of the epidermis and dermis are not changed compared to wild type mice showing that IL-4 has a subtle effect on skin thickening. In these mice, total or OVA-specific IgE levels significantly decrease, which argues against the roles of IgE in the pathogenesis of this mouse model. Correspondingly, OVA-sensitized IgE-deficient mice show no change in histological views of the skin tissues, infiltration of CD45+, CD3+, CD4+, and CD8+ cells and expression of IL-4, IL-5 and IFN-γ compared to OVA-sensitized wild-type mice (15), suggesting that this mouse model is independent of IgE. Furthermore, the redundancy of IL-4 and IL-13 *in vivo* may be the reason why the effects of IL-4–deficiency on skin thickening are subtle in

**2.1 Ovalbumin (OVA)-sensitized mice** 

this mouse model.

like lesions in this mouse model.

**2.2.1 IL-4 transgenic mice** 

various molecules associated with the pathogenesis of AD.

**2.1.1 Application of OVA-sensitized mouse model to IL-4–deficient mice** 

**2.1.2 Application of OVA-sensitized mouse model to IL-5–deficient mice** 

IL-4 or IL-13 that is sufficient to induce phenotypes similar to AD patients.

**2.2 Genetically engineered mice for Th2-type cytokines** 

IL-5–deficient mice had virtually no eosinophil (15). These mice sensitized with OVA had thinning of the epidermis and dermis compared with wild-type mice. However, infiltration of CD45+, CD3+, CD4+, and CD8+ cells and expression of chemokines were equivalent to wild-type mice. These results may suggest that IL-5 partially contributes to generating AD-

Thus far, transgenic mice that express IL-4 or IL-13 specifically in keratinocytes have mainly been generated using keratin promoters. In contrast to the IL-4-deficient mice, these gain-offunction mice manifest overt skin lesions, which indicates topical overexpression of either

Chan's group established and characterized IL-4 transgenic mice in which expression of IL-4 is controlled under the promoter of the keratin 14 gene (16-19). These mice are normal when they are newborn. However, almost four months after birth, they develop AD-like lesions such as xerosis (dry skin), conjunctivitis, and pruritic skin lesions (16). Many skin lesions appear in ears, necks, and eyes. Forty-three percent of the mice develop

in STAT6, a common critical transcription factor for IL-4 and IL-13 signals, exhibited skin lesions comparable to those of STAT6-positive littermates (13). Here, we summarize the results of analyses investigating the roles of Th2-type cytokines, using mice epicutaneously sensitized with allergens and genetically engineered mice (Table 1).


Table 1. Summary of effects of Th2-type cytokines in model mice
