Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes
Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes
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DOI：
10.4049/jimmunol.171.6.3262
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发表时间：
2003-09-15
影响因子：
4.4
通讯作者：
Leung, DYM
中科院分区：
文献类型：
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作者：
Nomura, I;Goleva, E;Leung, DYM
特应性皮炎（AD）和银屑病是两种最常见的慢性皮肤病。然而，患有AD而不是牛皮癣的患者经常遭受皮肤感染。为了了解这种现象的分子基础，使用基因芯片微阵列分析了AD和银屑病患者的皮肤活检。与银屑病皮肤相比，先天免疫应答基因人β防御素（HBD）-2，IL-8和诱导型NO合成酶（iNOS）的表达在AD中降低（HBD-2，p = 0.00021; IL-8，p = 0.044; iNOS，p = 0.016）。通过实时PCR（p = 0.0002）和免疫组织化学（p = 0.0005）在mRNA水平和蛋白水平证实了新型抗菌肽HBD-3的表达降低。通过实时PCR，我们的数据证实，与银屑病相比，AD与Th 2细胞因子的皮肤产生增加和促炎细胞因子如TNF-α、IFN-γ和IL-1 β水平降低有关。因为HBD-2、IL-8和iNOS已知被Th 2细胞因子抑制，我们检测了IL-4和IL-13对体外培养的角质形成细胞中HBD-3表达的影响。我们发现IL-13和IL-4抑制TNF-α和IFN-γ诱导的HBD-3产生。这些研究表明，抗微生物基因群的表达降低是由于在AD皮肤的炎症条件下Th 2细胞因子的局部上调和TNF-α和IFN-γ的量升高的缺乏而发生的。这些观察结果可以解释AD皮肤对微生物的易感性增加，并提出了一个新的基本规则，可以解释其他Th 2细胞介导的疾病中频繁感染的机制。
Atopic dermatitis (AD) and psoriasis are the two most common chronic skin diseases. However patients with AD, but not psoriasis, suffer from frequent skin infections. To understand the molecular basis for this phenomenon, skin biopsies from AD and psoriasis' patients were analyzed using GeneChip microarrays. The expression of innate immune response genes, human beta defensin (HBD)-2, IL-8, and inducible NO synthetase (iNOS) was found to be decreased in AD, as compared with psoriasis, skin (HBD-2, p = 0.00021; IL-8, p = 0.044; iNOS, p = 0.016). Decreased expression of the novel antimicrobial peptide, HBD-3, was demonstrated at the mRNA level by real-time PCR (p = 0.0002) and at the protein level by immunohistochemistry (p = 0.0005). By real-time PCR, our data confirmed that AD, as compared with psoriasis, is associated with elevated skin production of Th2 cytokines and low levels of proinflammatory cytokines such as TNF-alpha, IFN-gamma, and IL-1beta. Because HBD-2, IL-8, and iNOS are known to be inhibited by Th2 cytokines, we examined the effects of IL-4 and IL-13 on HBD-3 expression in keratinocyte culture in vitro. We found that IL-13 and IL-4 inhibited TNF-alpha- and IFN-gamma-induced HBD-3 production. These studies indicate that decreased expression of a constellation of antimicrobial genes occurs as the result of local up-regulation of Th2 cytokines and the lack of elevated amounts of TNF-alpha and IFN-gamma under inflammatory conditions in AD skin. These observations could explain the increased susceptibility of AD skin to microorganisms, and suggest a new fundamental rule that may explain the mechanism for frequent infection in other Th2 cytokine-mediated diseases.