異位性皮膚炎是一種受到環境刺激物的影響，而使得表皮障壁功能變差和出現表皮粗厚增生的慢性發炎皮膚疾病。異位性皮膚炎復發率相當高，但其詳細的致敏原因並不清楚。急性期的異位性皮膚炎，原駐足在皮膚表面的樹突狀細胞會呈現過敏原給naïve CD4+ T細胞，導致第二型輔助性T (Th2)細胞的分化，同時伴隨如介白素-4 (IL-4)和介白素-13 (IL-13)等Th2細胞激素的大量分泌。前述的細胞激素可透過角質細胞的活化和高度增生來促進過敏發炎反應的持續發生。相反的，在慢性期的異位性皮膚炎，naïve CD4+ T細胞的分化會從Th2轉變成Th1細胞。凝血酶調節素屬於第一型的穿膜醣蛋白，已被證實其參與調控表皮角質細胞的分化及傷口癒合。但角質細胞表現的凝血酶調節素在異位性皮膚炎中的角色至今未明。本研究首先使用IL-4或IL-13模擬異位性皮膚炎病理狀態的方式，來探討人類角質細胞株(HaCaT)在此疾病模式下，其凝血酶調節素的表現調控。結果顯示，當受到IL-4或IL-13刺激後，凝血酶調節素蛋白的表現會隨著濃度及時間增加而上升。此表現量的增加，是經由Akt及Stat-6而非ERK活化的抑制而受到調控。此外，本研究利用雞白蛋白(OVA)作為過敏原誘導，利用反覆經皮致敏的方式，建立一個已知的異位性皮膚炎小鼠模式。在此異位性皮膚炎小鼠模式中，我們發現其經皮水分散失量(TEWL)、胸腺基質淋巴生成素(TSLP)及血清中總免疫球蛋白E (IgE)皆有增加的現象。另外，利用組織學檢測亦發現，在誘導產生異位性皮膚炎的小鼠皮膚切片中，其表皮層及真皮層有明顯增厚的現象，並伴隨著較強的凝血酶調節素表現量。為了要確認凝血酶調節素在角質細胞中表現量的增強與異位性皮膚炎的嚴重程度關係，因此，我們培育了在角質細胞特異性剔除凝血酶調節素(K5-Cre/TMflox/flox)的小鼠。利用組織學檢測發現當利用OVA誘導角質細胞凝血酶調節素缺失的小鼠(K5-Cre/TMflox/flox)產生異位性皮膚炎疾病時，其表皮層中TSLP的表現量比起野生型對照組明顯變弱。更進一步也發現，在缺失小鼠中TEWL及總IgE量降低。由此結果顯示，在角質細胞中凝血酶調節素的缺失可能會降低異位性皮膚炎病灶處發炎的情況。綜合以上結果，角質細胞表現的凝血酶調節素與異位性皮膚炎的皮膚敏感度及疾病嚴重度呈正相關，角質細胞的凝血酶調節素可能藉由引發出高度活化的免疫狀態而導致異位性皮膚炎的發生。

Atopic dermatitis (AD), a chronic inflammatory skin disorder, results in defective skin barrier function and skin hyperplasia due to cutaneous hyperreactivity to environmental stimuli. AD can lead to significant morbidity and the reason remains unclear. In the acute phase of AD, skin-resident dendritic cells present allergens to naïve CD4+ T cells, thereby resulting in the development of T-helper 2 (Th2) cells as well as increased secretion of Th2 cytokines such as interleukin (IL)-4 and IL-13. Aforementioned cytokines trigger activation and hyperproliferation of keratinocytes, thereby promoting or sustaining allergic inflammation. In contrast, chronic AD contributes to switch of naïve CD4 T cell differentiation from Th2 to Th1. Thrombomodulin (TM), a type Ι transmembrane glycoprotein, has been demonstrated to play a role in epidermal keratinocyte differentiation and wound healing. However, the function of TM in AD is poorly investigated. In this study, we used IL-4/ IL-13 to mimic an AD-like state to investigate the regulation of TM in human keratinocyte HaCaT cells under this disease condition in vitro. We found that expression of TM was up-regulated by IL-4/ IL-13 stimulation in dose- and time-dependent manners. Furthermore, IL-4/ IL-13-induced TM expression in keratinocytes was regulated through Akt and Stat-6, but not ERK signaling pathways by using respective molecule inhibitors. In addition, we performed a well-known mouse model of AD induced by repeated epicutaneous sensitization of ovalbumin (OVA). We recapitalized AD disease phenotypes in OVA-challenged mice by observing elevated transepidermal water loss (TEWL), enhanced thymic stromal lymphopoietin (TSLP) expression and increased serum total IgE levels. Moreover, AD skin sections, compared to control ones, revealed remarkably hyperplasia of the epidermis with stronger TM expression by using histologic examination. To classify the contribution of TM in keratinocytes to the severity of AD, we established keratinocyte-specific TM deficient mice (K5-Cre/TMflox/flox mice). Histological examination revealed that the expression of TSLP, a keratinocyte-derived proinflammatory mediator, was significantly weaker in OVA-challenged K5-Cre/TMflox/flox mice than in wild type counterparts. Furthermore, levels of TEWL and serum IgE, were also decreased in OVA-challenged K5-Cre/TMflox/flox mice, suggesting the loss of TM in keratinocytes might reduce the inflammatory status in AD lesions. In conclusion, my data suggested that TM expression in keratinocytes is positively correlated with skin sensitization strength and AD severity. Keratinocytic TM might provoke a hyperactive immune status in the pathogenesis of AD.

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