Coronel Institute of Occupational Health, Academic Medical Center, Amsterdam, the Netherlands.
J Allergy Clin Immunol. 2012 Apr;129(4):1031-9.e1. doi: 10.1016/j.jaci.2011.12.989. Epub 2012 Feb 8.
Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (AD(FLG)) compared with that seen in patients with AD without these mutations (AD(NON-FLG)).
We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with AD(FLG) versus patients with AD(NON-FLG). We also sought to examine the same profiles in a murine model of filaggrin deficiency (Flg(ft)/Flg(ft) [Flg(delAPfal)] mice).
One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1α, IL-1β, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flg(ft)/Flg(ft) (Flg(delAPfal)) mice, separated from maFlg(ft)/maFlg(ft) (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1α, IL-1β, and IL-1RA.
SC IL-1 levels were increased in patients with AD(FLG); these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flg(ft)/Flg(ft) mice had upregulated expression of IL-1β and IL-1RA mRNA.
AD(FLG) is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches.
丝聚合蛋白（FLG）突变导致角质层（SC）天然保湿因子（NMF）成分减少，继而导致 SC pH 值升高。由于较高的 pH 值会激活 SC 蛋白酶活性，我们假设与无这些突变的特应性皮炎（AD）患者（AD（NON-FLG））相比，FLG 突变的特应性皮炎（AD）患者（AD（FLG））的角质细胞中促炎的白细胞介素-1（IL-1）细胞因子的释放会增强。
我们旨在研究正常皮肤中 AD（FLG）患者与 AD（NON-FLG）患者以及丝聚合蛋白缺陷型（Flg(ft)/Flg(ft)[Flg(delAPfal)]小鼠）模型中的 SC IL-1 细胞因子谱。
共研究了 137 例患者。使用共聚焦拉曼光谱法测定 NMF 水平；测定经皮水分流失和皮肤表面 pH 值。从 93 例患者的 SC 胶带条中测定白细胞介素-1α、白细胞介素-1β、白细胞介素-18、白细胞介素-1 受体拮抗剂（IL-1RA）和白细胞介素-8 水平。所有患者均筛查了 9 种 FLG 突变。从 maFlg(ft)/maFlg(ft)（鳞屑尾）小鼠中分离出 Flg(ft)/Flg(ft)（Flg(delAPfal)）小鼠，用于制备和培养原代鼠角质细胞，并作为鼠皮的来源。使用针对鼠白细胞介素-1α、白细胞介素-1β和白细胞介素-1RA 的引物进行 RT-PCR。
AD（FLG）患者的 SC IL-1 水平升高；这些水平与 NMF 水平呈负相关。NMF 值也与皮肤表面 pH 值呈负相关。Flg(ft)/Flg(ft) 小鼠的皮肤和角质细胞中白细胞介素-1β和白细胞介素-1RA mRNA 的表达上调。
AD（FLG）与 SC IL-1 细胞因子谱增加有关；这种谱也见于丝聚合蛋白缺陷的鼠同源物。这些发现可能对理解 FLG 突变对 AD 发病机制中炎症小体的影响以及帮助个体化治疗方法具有重要意义。
