Vestergaard C, Bang K, Gesser B, Yoneyama H, Matsushima K, Larsen C G
Department of Dermatology, Marselisborg Hospital, University of Aarhus, Aarhus, Denmark.
J Invest Dermatol. 2000 Oct;115(4):640-6. doi: 10.1046/j.1523-1747.2000.00115.x.
Atopic dermatitis is an inflammatory skin disease in which the inflammation is characterized by the influx of lymphocytes into the dermis. It is generally believed that atopic dermatitis is a Th2-type disease, i.e., the T lymphocytes produce interleukin-4, interleukin-5, interleukin-10, and interleukin-13, although it has become evident in recent years that the cytokine profile in the skin changes during the course of the disease towards a Th1-Th2 mixed cytokine profile (interferon-gamma, tumor necrosis factor alpha, and interleukin-2). The lymphocytes that home into the skin express cutaneous lymphocyte-associated antigen, and it has recently been shown that most of the lymphocytes in this population express the chemokine receptor CCR4. CCR4 is the receptor for the CC chemokine TARC (thymus and activation regulated chemokine), and this chemokine is expressed predominantly by keratinocytes in the basal layer of the epidermis of lesional atopic dermatitis skin in mice. In humans, however, it was shown to be expressed in the endothelial cells of the dermis. We have examined the peripheral blood mononuclear cells of atopic dermatitis patients for the expression of cutaneous lymphocyte-associated antigen and CCR4 and compared them with peripheral blood mononuclear cells from normal controls. We found that the proportion of CLA+CCR4+ lymphocytes is upregulated in atopic dermatitis patients. In addition we have examined skin biopsies of lesional and non-lesional skin from atopic dermatitis patients and found that the keratinocytes, but not the endothelial cells, produce TARC in the lesional but not in the nonlesional skin. To gain insight in the stimulatory mechanisms for TARC production in keratinocytes, as previously observed in mice, we cultured HaCaT cells and found that interferon-gamma and tumor necrosis factor alpha work synergistically to induce TARC production. These observations suggest that the induction of TARC production in keratinocytes plays an important role in the late phase skin invasion by CCR4+CLA+ Th2-type lymphocytes in atopic dermatitis.
特应性皮炎是一种炎症性皮肤病，其炎症特征是淋巴细胞流入真皮。一般认为特应性皮炎是一种Th2型疾病，即T淋巴细胞产生白细胞介素-4、白细胞介素-5、白细胞介素-10和白细胞介素-13，尽管近年来已明显发现，在疾病过程中皮肤中的细胞因子谱会朝着Th1-Th2混合细胞因子谱（干扰素-γ、肿瘤坏死因子α和白细胞介素-2）转变。归巢至皮肤的淋巴细胞表达皮肤淋巴细胞相关抗原，最近有研究表明，该群体中的大多数淋巴细胞表达趋化因子受体CCR4。CCR4是CC趋化因子TARC（胸腺和活化调节趋化因子）的受体，这种趋化因子主要由小鼠特应性皮炎皮损皮肤表皮基底层的角质形成细胞表达。然而，在人类中，它被证明在真皮内皮细胞中表达。我们检测了特应性皮炎患者外周血单个核细胞中皮肤淋巴细胞相关抗原和CCR4的表达，并将其与正常对照的外周血单个核细胞进行比较。我们发现，特应性皮炎患者中CLA+CCR4+淋巴细胞的比例上调。此外，我们还检测了特应性皮炎患者皮损和非皮损皮肤的活检样本，发现角质形成细胞而非内皮细胞在皮损皮肤而非非皮损皮肤中产生TARC。为了深入了解角质形成细胞中TARC产生的刺激机制，正如之前在小鼠中观察到的那样，我们培养了HaCaT细胞，发现干扰素-γ和肿瘤坏死因子α协同作用诱导TARC产生。这些观察结果表明，角质形成细胞中TARC产生的诱导在特应性皮炎中CCR4+CLA+ Th2型淋巴细胞晚期皮肤浸润中起重要作用。
