Invited Review Article
Thymus and activation regulated chemokine (TARC)/CCL17 and skin diseases

https://doi.org/10.1016/j.jdermsci.2006.06.002Get rights and content

Summary

Thymus and activation-regulated chemokine (TARC)/CCL17 is constitutively expressed in the thymus and is produced by dendritic cells (DC), endothelial cells, keratinocytes (KC) and fibroblasts. TARC is designated a Th2 type chemokine since it binds to CCR4. We review the pathogenic role of TARC in skin diseases such as atopic dermatitis (AD), bullous pemphigoid (BP) and mycosis fungoides (MF) focusing on epidermal KC and Langerhans cells (LC), which are epidermal DC. We have determined that serum TARC levels sharply reflect the disease activity of AD, which is thought to be a Th2-dominant inflammatory skin disease especially in the acute phase. Serum TARC levels are also related to the disease activity of BP, which is a blistering autoimmune skin disease, and MF, which is a cutaneous T-cell lymphoma, but very high serum TARC levels are only seen in a limited number of various other skin diseases. TARC may be a useful laboratory marker for the diagnosis of AD, especially cases which are moderate to severe, and for the evaluation of disease activity of AD. IL-4 and TGF-β1 downregulate TNF-α and IFN-γ induced TARC production in the human KC cell line, HaCaT cells, while IL-4 upregulates, and IFN-γ downregulates TARC production by mouse LC. Because TARC and its receptor CCR4 are believed to play important roles in the pathogenesis of AD, BP and MF, TARC and CCR4 may be possible future targets for therapy of these diseases.

Introduction

Chemokines are small, secreted molecules that regulate leukocyte trafficking. The human chemokine system currently includes more than 50 chemokines and 18 chemokine receptors. Based on the position of the first two of the four conserved cysteine residues, chemokines are divided into four subfamilies: CXC, CC, C and CX3C [1]. Chemokines bind to leukocytes via their corresponding seven transmembrane-spanning, G-protein coupled receptors that have been grouped according to the structure of their chemokine ligands (CXCR, CCR, XCR and CX3CR).

Chemokines can be divided into two categories in terms of their physiological features, inflammatory and homeostatic [2]. Inflammatory chemokines are expressed in inflamed tissues on stimulation by pro-inflammatory cytokines. These chemokines are specialized for the recruitment of effector cells, including monocytes, granulocytes and effector T cells. In contrast, homeostatic chemokines are produced in discrete microenvironments within lymphoid or non-lymphoid tissues such as the skin and mucosa. These constitutively produced chemokines are involved in maintaining physiological traffic and positioning of cells during immune surveillance [23]. Inflammatory chemokines include MCP-1 (monocyte chemoattractant protein-1/CCL2), MIP-1α (macrophage inflammatory protein-1 α/CCL3), RANTES (regulated on activation, normal T-cell expressed and secreted/CCL5), eotaxin/CCL11, Mig (monokine induced by interferon-γ/CXCL9), IP-10 (interferon-γ inducible protein-10/CXCL10), I-TAC (interferon-inducible T-cell α chemoattractant/CXCL11), etc., while homeostatic chemokines include SDF-1 (stromal cell-derived factor-1/CXCL12), BCA-1 (B cell-activating chemokine 1/CXCL13), ELC (EB virus-induced receptor ligand chemokine/CCL19), SLC (secondary lymphoid tissue chemokine/CCL21), etc. TARC (thymus and activation-regulated chemokine/CCL17) and MDC (macrophage-derived chemokine/CCL22) are assumed to belong to both subfamilies of chemokines.

It has been shown that several chemokine receptors are expressed preferentially in the Th1 (CXCR3, CCR5) and Th2 (CCR3, CCR4 and CCR8) subsets of the helper T cells [3]. In particular, expression of CXCR3 and CCR4 are highly specific for Th1 and Th2 cells, respectively. Mig, IP-10 and I-TAC are called Th1 type chemokines because they are the ligands for CXCR3. On the other hand, TARC and MDC are designated Th2 type chemokines since they bind to CCR4.

TARC is a member of the CC chemokine group that is constitutively expressed in the thymus and is produced by dendritic cells (DC) [4], [5], endothelial cells [6], keratinocytes (KC) [7], bronchial epithelial cells [8] and fibroblasts [9]. It is a ligand for CCR4, which is predominantly expressed on Th2 lymphocytes, basophils and natural killer cells [3], [10], [11]. In this article, we review the pathogenic role of TARC in skin diseases such as atopic dermatitis (AD), bullous penphigoid (BP) and mycosis fungoides (MF) focusing on epidermal KC and Langerhans cells (LC).

Section snippets

Atopic dermatitis (AD)

AD is a chronic inflammatory skin disease that is characterized by pruritic and eczematous lesions and is associated with elevated serum IgE levels, specific IgE environmental allergens such as house dust mites, and tissue and peripheral blood eosinophilia [12]. AD is characterized by the predominant infiltration of Th2-type cells, the increased secretion of the Th2-related cytokines interleukin (IL)-4 and IL-5 in the acute phase of lesional skin [13], and the high responsiveness of peripheral

Polymorphisms of TARC gene

The TARC gene is located at chromosome 16q13 [28], where total serum IgE concentration has been reportedly linked [29]. A high concentration of serum TARC is reported in patients with allergic diseases such as AD [16] and bronchial asthma (BA) [30]. Thus, a single nucleotide polymorphism (SNP) of TARC/CCL17 gene is a candidate as one of the genetic factors in these allergic diseases.

We performed polymorphism screening of the coding and promoter regions of the TARC gene, and found two rare

Regulation of TARC production by keratinocytes (KC)

It has been reported from in vitro studies that PAM 212 cells, a murine KC cell line, and normal human KC produced TARC after stimulation with TNF-α and IFN-γ [7], [33]. Consistent with these in vitro data, it was disclosed that TARC is expressed in the lesional KC of AD skin, suggesting that KC is one of the main sources of TARC [16], [33]. We also showed immunoreactive TARC in the lesional KC of BP patients and high fluid TARC levels in these patients, suggesting that lesional KC produce TARC

Regulation of TARC production by Langerhans cells (LC)

DC are antigen-presenting cells with a unique ability to stimulate naïve T cells. LC are a specific subtype of DC localized in the epidermis. LC differ from other DC in possessing Birbeck granules, lacking functional mannose receptors, expressing E-cadherin, and being dependent on TGF-β for their differentiation [43]. We succeeded in preparing highly purified LC (>95%) from BALB/c mice by applying the panning method [44]. As for functional characteristics of LC in comparison with those of

Conclusion

We have determined that serum TARC levels sharply reflect the disease activity of AD, which is thought to be a Th2-dominant inflammatory skin disease especially in the acute phase. Serum TARC levels are also related with the disease activity of BP and MF, but very high serum TARC levels are only seen in a limited number of other skin diseases. TARC may be a useful laboratory marker for the diagnosis of AD, especially cases which are moderate to severe, and for the evaluation of disease activity

Hidehisa Saeki received his MD and PhD degrees from Tokyo University, Tokyo, Japan in 1991 and 1997, respectively. During 1998–2000, he was a visiting fellow at the National Cancer Institute, Bethesda, MD. He is currently an assistant professor at the Department of Dermatology, Tokyo University. His current interests are in pathogenic roles of chemokines in skin diseases such as atopic dermatitis and psoriasis vulgaris.

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    Hidehisa Saeki received his MD and PhD degrees from Tokyo University, Tokyo, Japan in 1991 and 1997, respectively. During 1998–2000, he was a visiting fellow at the National Cancer Institute, Bethesda, MD. He is currently an assistant professor at the Department of Dermatology, Tokyo University. His current interests are in pathogenic roles of chemokines in skin diseases such as atopic dermatitis and psoriasis vulgaris.

    Kunihiko Tamaki received his MD and PhD degrees from the University of Tokyo, Tokyo, Japan in 1973 and 1983, respectively. During 1985–1988, he was an associate professor at the Department of Dermatology, the University of Tokyo. During 1988–1994, he was a professor and chairman, Department of Dermatology, Yamanashi Medical College. He is currently a professor and chairman, Department of Dermatology, Faculty of Medicine, the University of Tokyo.

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