Ghaffar O, Christodoulopoulos P, Lamkhioued B, Wright E, Ihaku D, Nakamura Y, Frenkiel S, Hamid Q
Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
Clin Exp Allergy. 2000 Jan;30(1):86-93. doi: 10.1046/j.1365-2222.2000.00781.x.
The allergen-induced late nasal response is associated with a high local expression of interleukin (IL) -4, a TH2-type cytokine implicated in immunoglobulin (Ig) E production, tissue eosinophilia and other events considered to be relevant to allergic inflammation. Interaction of IL-4 with its receptor activates at least two distinct signalling pathways that culminate in the transcription of specific target genes. One pathway involves the activation of a transcription factor termed signal transducer and activator of transcription factor 6 (STAT6).
To investigate the expression of STAT6 in the allergen-induced late nasal response and to examine the effect of local steroid treatment on STAT6 expression.
Inferior turbinate biopsies were obtained from subjects with allergic rhinitis out of the allergen season. Subjects were then randomized into topical steroid- (n = 6) and placebo-treated (n = 6) groups in a double-blind fashion. After a 6-week treatment period, a second nasal biopsy was performed 24 h after local challenge with allergen. STAT6 immunoreactivity was examined in biopsy specimens by immunocytochemistry using a specific monoclonal antibody. Numbers of inflammatory cells (CD3+ T cells and MBP+ eosinophils) and IL-4 mRNA+ cells were investigated by immunocytochemistry and in situ hybridization, respectively.
STAT6 immunoreactivity was detected in all biopsies studied and localized predominantly to inflammatory tissue of the nasal mucosa. After allergen challenge, expression of STAT6 was markedly increased in placebo-treated patients (P < 0.01). By confocal microscopy, STAT6 was localized to the cytoplasm and the nucleus of positively-staining cells. The allergen-induced increase in STAT6 immunoreactive cells was not observed in the steroid-treated patients. The change in STAT6 immunoreactivity after allergen challenge correlated significantly with the change in numbers IL-4 mRNA+ cells (r = 0.74, P = 0.006) and CD3+ T cells (r = 0.76, P = 0. 004), but not MBP+ eosinophils.
This study provides the first evidence of increased STAT6 expression in vivo in human allergic inflammation. The results support a role for STAT6 and IL-4 in the pathogenesis of late nasal response and show that decreases in STAT6 expression parallel the reduction in IL-4 expression that occurs with topical steroid treatment.
变应原诱导的鼻黏膜迟发反应与白细胞介素（IL）-4的高局部表达相关，IL-4是一种TH2型细胞因子，与免疫球蛋白（Ig）E产生、组织嗜酸性粒细胞增多及其他被认为与变应性炎症相关的事件有关。IL-4与其受体相互作用激活至少两条不同的信号通路，最终导致特定靶基因的转录。其中一条通路涉及一种称为信号转导及转录激活因子6（STAT6）的转录因子的激活。
研究STAT6在变应原诱导的鼻黏膜迟发反应中的表达，并观察局部应用类固醇治疗对STAT6表达的影响。
在非变应原季节从变应性鼻炎患者获取下鼻甲活检组织。然后将受试者以双盲方式随机分为局部应用类固醇治疗组（n = 6）和安慰剂治疗组（n = 6）。经过6周治疗期后，在局部用变应原激发24小时后进行第二次鼻活检。使用特异性单克隆抗体通过免疫细胞化学检测活检标本中的STAT6免疫反应性。分别通过免疫细胞化学和原位杂交研究炎症细胞（CD3+ T细胞和髓鞘碱性蛋白（MBP）+嗜酸性粒细胞）数量及IL-4 mRNA+细胞数量。
在所研究的所有活检组织中均检测到STAT6免疫反应性，且主要定位于鼻黏膜的炎症组织。变应原激发后，安慰剂治疗患者的STAT6表达明显增加（P < 0.01）。通过共聚焦显微镜检查，STAT6定位于阳性染色细胞的细胞质和细胞核。在类固醇治疗患者中未观察到变应原诱导的STAT6免疫反应性细胞增加。变应原激发后STAT6免疫反应性的变化与IL-4 mRNA+细胞数量的变化（r = 0.74，P = 0.006）和CD3+ T细胞数量的变化（r = 0.76，P = 0.004）显著相关，但与MBP+嗜酸性粒细胞数量无关。
本研究首次提供了人类变应性炎症中体内STAT6表达增加的证据。结果支持STAT6和IL-4在鼻黏膜迟发反应发病机制中的作用，并表明STAT6表达的降低与局部应用类固醇治疗时IL-4表达的减少平行。
