Regulation of Th9-type pulmonary immune responses: a new role for COX-2.
Regulation of Th9-type pulmonary immune responses: a new role for COX-2.
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DOI：
10.1164/rccm.201302-0205ed
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发表时间：
2013-04
影响因子：
24.7
通讯作者：
J. Boyce;R. Peebles
中科院分区：
文献类型：
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作者：
J. Boyce;R. Peebles
前列腺素(PGs)是环氧合酶(COX)代谢花生四烯酸的普遍产物。五种结构和功能不同的PG(PGE2、PGF2、PGI2、PGD2和血栓素A2)以细胞和组织特异性的方式从COX衍生的前体PGH2形成，后者由特定的末端合成酶(1)转化为最终产物。每一种PG都与广泛的体内平衡功能有关，包括血栓形成、维持血管张力和血流以及修复上皮细胞表面。大多数也与炎症有关；事实上，COX抑制剂是治疗炎症性疾病的最古老和最成功的靶向治疗方法之一，目前仍被广泛用于控制疼痛、发烧和肿胀。这些药物还会损害前列腺素的体内平衡功能所需的前列腺素的合成，这可能是它们一些不受欢迎的副作用的原因。尽管前列腺素在大多数器官系统中发挥促炎作用，但它们在肺中的作用主要是保护和抗炎。在人类中最明显的例子是大约5%-10%的哮喘患者在服用非选择性COX抑制剂(阿司匹林加重的呼吸系统疾病)后出现支气管收缩(2)。这些个体表现出明显的鼻窦和支气管粘膜表面的嗜酸性炎症，以及鼻腔粘膜中COX-2同工酶的表达受损(3)。在小鼠中，药物抑制COX-1和/或COX-2或任何一种酶的基因缺失会导致变应原致敏和激发后嗜酸性粒细胞增多和支气管血管病变(4-6)。最近，在特定PG合成酶和PGs受体中定向缺失的小鼠的使用表明，PGE2和PGI2在调节肺部对过敏原的免疫反应以及终端器官对炎症状态的反应中分别发挥作用(7，8)。这些和其他PGs的受体在先天和获得性免疫系统的细胞上的广泛分布表明PGs有多个潜在的免疫靶点和作用，其中大多数还没有确定。辅助性T细胞9(Th9)是最近描述的一种产生IL-9和IL-10(以前被认为是Th2型细胞因子)的CD4+T细胞亚群(图1)(9)。Th9细胞在IL-4和转化生长因子β的刺激下由原始T细胞分化而来，表达B型IL-17受体(IL-17RB)。IL-17RB配体IL-25可增强Th9细胞产生IL-9(肥大细胞扩张和呼吸道反应性的有效诱导剂)。在这一期的期刊中，Li和他的同事(第812-822页)展示了COX-2衍生的PGE2和PGD2在控制Th9的体外和体内发育中具有显著的动态平衡功能(11)。使用传统的卵清蛋白致敏和激发模型，作者证明，与野生型对照相比，缺乏COX-2的小鼠，而不是那些缺乏COX-1的小鼠，血液、肺、支气管肺泡灌洗液和肺引流淋巴结中的Th9细胞数量增加。当在体外有利于Th9的条件下极化时，幼稚的CD4+T细胞中缺乏内源性COX-2会增强其IL-9和其他Th9谱系标记的表达。使用互补方法的组合，作者证明了两种前列腺素，PGE2(作用于E前列腺素[EP]2和EP4受体)和PGD2(作用于D前列腺素[DP]2受体)在体外和体内可以通过抑制IL-17RB的表达来抑制Th9细胞的发育(图1)。最后，他们发现，在体外，PGE2和PGD2抑制了人类幼稚T细胞的Th9发育。图1.当在转化生长因子-β和IL-4存在下被激活时，幼稚的CD_4细胞分化为Th9细胞。(A)Th9细胞产生IL-9。(B)IL-25通过其由IL-17 A型受体(IL-17RA)和IL-17RB组成的异二聚体受体发出信号，增强...Li和他的同事的研究证明了内源性COX-2产物在体内调节T辅助细胞极化方面的全新作用，并将这一发现转化为人类细胞。鉴于IL-9在几种过敏性疾病中的隐含作用，包括哮喘(12例)、特应性皮炎(13例)和食物过敏(14例)，两种COX产品控制Th9的发展的发现对人类疾病的病理生物学和治疗具有令人兴奋的潜在意义。吸入前列腺素E_2可阻止过敏原激发的特应性患者(15例)和阿司匹林刺激的阿司匹林加重的呼吸道疾病患者(16例)的肺部晚期反应，人们很容易推测Th9细胞上的EP2和EP4受体是这些作用的靶点。像Th9细胞一样，最近发现的先天辅助细胞2型(ILC2)群体(它产生大量的IL-5、IL-13，有趣的是，在过敏性炎症中产生IL-9)需要表达IL-17RB和存在IL-25，也表达DP2受体(17)。EP和/或DP受体信号是否像在Th9细胞那样通过调节IL-17RB的表达来控制ILC2的功能仍有待确定。最后，这项研究进一步复杂化了PGD2的功能，根据所使用的模型和涉及的受体，PGD2对过敏原诱导的肺部炎症是诱导(18)还是抑制(19)。在靶向激动剂和拮抗剂应用于人类变态反应性疾病之前，了解PGs的相关受体和靶点是必要的步骤。
Prostaglandins (PGs) are ubiquitous products of arachidonic acid metabolism by the cyclooxygenase (COX) enzymes. Five structurally and functionally distinct PGs (PGE2, PGF2, PGI2, PGD2, and thromboxane A2) form in a cell- and tissue-specific manner from the COX-derived precursor, PGH2, which is converted to end products by specific terminal synthases (1). Each PG is implicated in a broad range of homeostatic functions, including thrombosis, maintenance of vascular tone and blood flow, and repair of epithelial surfaces. Most have also been implicated in inflammation; indeed, COX inhibitors are one of the oldest and most successful target-based treatments for inflammatory diseases, and are still used widely to control pain, fever, and swelling. These drugs also impair the synthesis of PGs needed for homeostatic functions of PGs, likely accounting for some of their unwanted side effects. Although PGs play proinflammatory roles in most organ systems, their role in the lungs is largely protective and antiinflammatory. The most obvious example in humans is the approximately 5–10% of asthmatic individuals who develop bronchoconstriction with the administration of nonselective COX inhibitors (aspirin-exacerbated respiratory disease) (2). These individuals exhibit marked eosinophilic inflammation of the sinonasal and bronchial mucosal surfaces, along with impaired expression of the COX-2 isoenzyme in their sinonasal mucosa (3). In mice, pharmacologic inhibition of COX-1 and/or COX-2 or genetic deletion of either enzyme results in enhanced eosinophilia and bronchovascular pathology after allergen sensitization and challenge (4–6). More recently, the use of mice with targeted deletions in specific PG synthases and receptors for PGs has implicated separate roles for PGE2 and PGI2 in regulating pulmonary immune responses to allergen, as well as end-organ responsiveness to the inflammatory state (7, 8). The broad distribution of receptors for these and other PGs on cells of the innate and adaptive immune systems suggests multiple potential immunologic targets and effects of PGs, most of which have not been defined. T-helper 9 (Th9) cells are a recently described subset of CD4+ T cells that generate IL-9 and IL-10 (previously thought to be Th2-type cytokines) (Figure 1) (9). Th9 cells develop from naive T cells as a result of stimulation by IL-4 and transforming growth factor β, and express the type B IL-17 receptor (IL-17RB). The IL-17RB ligand, IL-25, amplifies the production of IL-9 (a potent inducer of mast cell expansion and airway reactivity) (10) by Th9 cells. In this issue of the Journal, Li and colleagues (pp. 812–822) demonstrate a marked homeostatic function for COX-2–derived PGE2 and PGD2 in the control of Th9 development in vitro and in vivo (11). Using a traditional model of ovalbumin sensitization and challenge, the authors demonstrate that mice lacking COX-2, but not those lacking COX-1, display increased numbers of Th9 cells in the blood, lung, bronchoalveolar lavage fluid, and lung-draining lymph nodes relative to wild-type controls. The absence of endogenous COX-2 in naive CD4+ T cells amplifies their expression of IL-9 and other Th9 lineage markers when polarized under Th9-favoring conditions in vitro. Using a combination of complementary approaches, the authors demonstrated that two PGs, PGE2 (acting at E prostanoid [EP]2 and EP4 receptors) and PGD2 (acting at D prostanoid [DP]2 receptors) could suppress Th9-cell development in vitro and in vivo by suppressing the expression of the IL-17RB (Figure 1). Finally, they showed that PGE2 and PGD2 suppressed Th9 development from naive human T cells in vitro. Figure 1. Naive CD4 cells differentiate into Th9 cells when activated in the presence of TGF-β and IL-4. (A) Th9 cells produce IL-9. (B) IL-25, signaling through its heterodimeric receptor consisting of IL-17 receptor type A (IL-17RA) and IL-17RB, augments ... The study by Li and colleagues demonstrates a completely novel role for endogenous COX-2 products in regulating T-helper cell polarization in vivo, and translates the findings in mice to human cells. Given the implied role for IL-9 in several allergic diseases, including asthma (12), atopic dermatitis (13), and food allergy (14), the discovery that two COX products control Th9 development has exciting potential implications for pathobiology and treatment of human disease. Inhaled PGE2 blocks pulmonary late-phase reactions in allergen-challenged atopic individuals (15) and aspirin-challenged subjects with aspirin-exacerbated respiratory disease (16), and it is tempting to speculate that EP2 and EP4 receptors on Th9 cells are among the targets responsible for these effects. Like Th9 cells, the recently identified innate helper cell type 2 (ILC2) population (which generates large quantities of IL-5, IL-13, and, interestingly, IL-9 in allergic inflammation) requires expression of IL-17RB and the presence of IL-25, and also expresses DP2 receptors (17). Whether EP and/or DP receptor signaling controls ILC2 functions by regulating IL-17RB expression as it does in Th9 cells remains to be determined. Lastly, the study further complicates the functions of PGD2, which is either inductive (18) or suppressive (19) of allergen-induced pulmonary inflammation depending on the model used and the receptor involved. Understanding the full range of relevant receptors and targets of PGs is a necessary step before the application of targeted agonists and antagonists to human allergic disease.