维A酸结合蛋白的作用及其调节

随着维A酸类药物在临床上的广泛应用，对维A酸作用机制及其分子机制的探讨也越来越深入。近些年的研究表明维A酸结合蛋白在维A酸代谢和胞内信号转导等一系列过程中发挥着重要作用，而且维A酸结合蛋白与维A酸及其他因素之间均存在复杂的调控关系，他们之间的相互作用调节着细胞的生长和分化。     

维A酸在皮肤科领域的研究新进展

维A酸在皮肤科领域有着广泛的用途及进一步开发应用的前景。一般认为在体内维A酸主要是通过两类维A酸核受体共6种亚型发挥作用的，在此方面已进行了大量的研究，受体选择性维A酸的出现并应用于临床就是此方面研究的成果。另一方面，近期的研究证明维A酸对某些疾病的治疗作用至少有一部分是通过非受体依赖途径实现的。因此，维A酸在体内作用的具体机制尚待进一步的研究。     

天然维A酸—视黄醛在皮肤病中的应用

维A酸在皮肤病中的作用非常广泛，但由于局部刺激，一定程度上限制了其临床应用。视黄醛是天然维A酸的中间代谢产物，具有与维A酸相似的生物学活性，而且皮肤对它的耐受性明显优于维A酸。现综述视黄醛在体内及皮肤中的代谢及其生物学活性和在皮肤科中的应用。     

维A酸类药物在痤疮治疗中的应用

正维A酸类药物在痤疮药物治疗中举足轻重,但临床医生对其作用机制、临床适应证、不良反应及使用方法等仍缺乏足够的认识,甚至存在许多误区,导致应用受限。本文简要概述维A酸在痤疮应用中的有关问题。1外用维A酸1.1作用机制痤疮治疗中有效的外用维A酸包括第一代的全反式维A酸、9顺-维A酸、13顺-维A酸(异维A酸)、维胺酯及第三代的阿达帕林、他扎罗汀等。主要作用机制有:(1)抗毛囊皮脂腺导管     

维A酸结合蛋白的作用及其调节

随着维A酸类药物在临床上的广泛应用,对维A酸作用机制及其分子机制的探讨也越来越深入。近些年的研究表明维A酸结合蛋白在维A酸代谢和胞内信号转导等一系列过程中发挥着重要作用,而且维A酸结合蛋白与维A酸及其他因素之间均存在复杂的调控关系,他们之间的相互作用调节着细胞的生长和分化。     

全反式维A酸对皮肤鳞癌细胞增殖影响实验研究

目的探讨全反式维A酸对体外培养皮肤鳞癌细胞增殖的影响。方法传代培养皮肤鳞癌细胞,不同浓度维A酸作用后,MTT法观察维A酸对细胞增殖的影响,流式细胞仪进行细胞凋亡及周期分析。结果低浓度维A酸作用后细胞增殖率高于对照组,其中1μM浓度组作用最强,而高浓度维A酸作用后细胞增殖率低于对照组,且呈剂量依赖性抑制;ATRA不能诱导A431细胞发生显著凋亡;维A酸对皮肤鳞癌细胞的促进增殖作用可能与S期细胞数百分比增多有关。结论全反式维A酸对体外皮肤鳞癌细胞的增殖抑制作用有严格的剂量范围,为皮肤鳞癌的临床治疗提供实验依据。     

倍扎罗汀及其在皮肤科的应用

倍扎罗汀是一种合成的维A酸X受体激动剂，与维A酸X受体高度特异性结合，主要通过影响与维A酸X受体形成异二聚体的多种细胞核受体发挥调节细胞生长、增殖与分化的作用。近年来，随着系统和局部应用适应证的不断扩大，其作用机制的研究也日益深入。     

维A酸在皮肤科领域的研究新进展

维A酸在皮肤科领域有着广泛的用途及进一步开发应用的前景。一般认为在体内维A酸主要是通过两类维A酸核受体共 6种亚型发挥作用的 ,在此方面已进行了大量的研究 ,受体选择性维A酸的出现并应用于临床就是此方面研究的成果。另一方面 ,近期的研究证明维A酸对某些疾病的治疗作用至少有一部分是通过非受体依赖途径实现的。因此 ,维A酸在体内作用的具体机制尚待进一步的研究。     

维A酸受体在皮肤生理中的作用

维A酸受体属于细胞核受体超家族成果，在皮肤的分化、增殖、炎症过程中发挥重要作用。现就维A酸受体在皮肤生理中的作用进行文献综述。     

全反式维A酸对HaCaT细胞中皮肤屏障相关因子Flg及Klf4的影响

目的研究全反式维A酸作用于人角质形成细胞HaCaT细胞后,通过分子水平检测Flg及Klf4的变化,以明确维A酸对皮肤屏障相关因子的影响及可能分子机制。方法 1μmol/L的全反式维A酸作用HaCaT 36h后,检测Flg,Klf4在基因及蛋白水平的变化。结果全反式维A酸作用HaCaT细胞36h后,实时定量PCR法及免疫印迹技术结果显示实验组Flg,Klf4表达下降。结论全反式维A酸作用于HaCaT细胞后,引起Flg及Klf4在基因及蛋白水平表达的下调,从分子生物学角度提示全反式维A酸可引起皮肤屏障的破坏。     

Sebocytes contribute to skin inflammation by promoting the differentiation of T helper 17 cells

The main function of cells in the skin called sebocytes is considered to be the production of lipids (oils) to moisturize the skin. It used to be thought that they were bystander cells during skin inflammation with no impact on the body's immune response, meaning they did not help the body to fight off signs of infection on inflammation. However, it recently became apparent that sebocytes do in fact respond to signs of inflammation (proinflammatory stimuli) as well as the presence of bacteria, and they release tiny protein molecules called chemokines and cytokines which play a role in inflammation. This discovery prompted scientists from Germany and Hungary to examine samples of skin with acne and skin without acne, to see if sebocytes also have any influence over white blood cells of the immune system (immune cells). The researchers found that sebocytes do indeed participate in inflammatory processes in the skin by recruiting and communicating with immune cells, and this interaction leads to the generation of Th17 cells. Further studies have to clarify whether this relationship between sebocytes and Th17 cells helps the immune system or, on the contrary, contributes to the development not only of acne, but also of several inflammatory skin diseases.     

IL-10 secretion of allergen-specific skin-derived T cells correlates positively with that of the Th2 cytokines IL-4 and IL-5*

Abstract In atopic individuals, allergen-specific CD4+ T lymphocytes often belong to the T-helper 2 (Th2) subset as they secrete the marker cylokincs interleukin-4 (IL-4) and IL-5 but not intcrfcron-y (INF-y). IL-10 is a cytokine the production of which, in the mouse system has been described to be restricted to the Th2 subset, but in the human was found to be produced by both ThI and Th2 T cell clones (TCC). We have recently shown that house dust mite antigen (Dermatophagoides pteron-yssinus)-specific TCC isolated from skin of patients with atopic dermatitis have a more polarized Th2 cytokine production profile than TCC obtained from the peripheral blood of these patients. In this study, we report that skin-derived TCC secrete more IL-10, IL-4 and IL-5, than TCC isolated from the blood of the same individual (p < 0.05). The difference was more significant with specific TCC than with non-specific TCC. Furthermore, there was a positive correlation between the production of IL-10 and that of IL-4 and IL-5, respectively. In addition, the amount of IL-4 and IL-5 secreted by specific TCC from the skin correlated positively. These results were confirmed by the detection of mRNA by PCR. Finally, our data confirm that in human blood-derived TCC IL-10 secretion is not related to a particular cytokine production profile. We suggest that the skin of AD provides an unique environment for the development of aTh2-likc secretion pattern not only with respect to IL-4 and IL-5 but also regarding IL-10.     

Paradoxical increase in skin inflammation in the absence of CCR4

The chemokine receptors are seven transmembrane, G-protein-coupled surface receptors that play key roles in the migration and localization of leukocytes to the skin during physiologic and inflammatory states. Their ligands, chemokines, are small secreted proteins that initiate leukocyte chemoattraction. Recent data indicate that known subsets of T helper (Th) cells express signature chemokine receptors (e.g., CXCR3, CCR3/4, and CCR6) that help to define individual subsets such as Th1, Th2, and Th17 cells, respectively, although there is some degree of overlap among these T-cell subsets. In this issue, Lehtim?ki et al. use an oxazolone-induced contact hypersensitivity (CHS) model to show that T cells (as well as neutrophils and eosinophils) from CCR4(-/-) mice accumulate just as (if not more) efficiently in inflamed skin as compared with the same population of leukocytes from wild-type (WT) mice. Although somewhat unexpected, their results can be explained if CCR4 attracts both proinflammatory and suppressive T cells into skin in addition to serving functions that are partially redundant with those of CCR10. Finally, we discuss other possible roles for CCR4 in the homing of T cells to skin.     

Th17细胞与银屑病

银屑病是一种Th1细胞免疫反应介导的慢性炎症性皮肤病.近年发现一种新型的CD4+效应性T细胞--Th17细胞,不同于Th1和Th2细胞,特异性产生IL-17,在许多既往归类于Th1介导的慢性炎症性疾病中(包括银屑病)发挥重要作用.文中将介绍Th17细胞免疫反应在银屑病发病中的作用,同时介绍其在目前银屑病治疗方法中的意义和在新的潜在治疗靶位中的前景.     

Low herpesvirus entry mediator (HVEM) expression on dermal fibroblasts contributes to a Th2-dominant microenvironment in advanced cutaneous T-cell lymphoma

LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes) is a ligand for HVEM. LIGHT-HVEM interactions are important in T helper type 1 (Th1) immune responses. In some cases with early stages of cutaneous T cell lymphoma (CTCL), IL-2, IFN-γ, and Th1 chemokines are expressed in lesional skin, while IL-4, IL-5, and Th2 chemokines are dominant in advanced CTCL. In this study, we investigated roles of LIGHT and HVEM in the microenvironment of CTCL. LIGHT enhanced production of Th1 chemokines, such as CXC chemokine ligand (CXCL) 9, CXCL10, and CXCL11, from IFN-γ-treated dermal fibroblasts via phosphorylation of inhibitor κBα. Messenger RNA levels of these chemokines were increased in lesional skin of early CTCL. Interestingly, while LIGHT expression in CTCL skin correlated with disease progression, HVEM expression was significantly decreased in advanced CTCL skin. HVEM was detected in dermal fibroblasts in early CTCL skin, but not in advanced CTCL skin in situ. These results suggest that low HVEM expression on dermal fibroblasts in advanced CTCL skin attenuates expression of Th1 chemokines, which may contribute to a shift to a Th2-dominant microenvironment as disease progresses.     

Why does allergic contact dermatitis exist?

The skin immune system’s propensity to produce allergic contact dermatitis (ACD) to harmless chemicals, while otherwise being an efficient defence system, represents a dermatological paradox. We postulate that a major role in signalling in ACD is played by Toll‐like receptor (TLR)2 and TLR4, and arises from their activation by extracellular danger‐associated molecular patterns (DAMPs). Ligand activation of TLR4/2 results in the expression of interleukins (ILs) IL‐1β, IL‐6, IL‐12, IL‐18 and IL‐23, tumour necrosis factor‐α and interferon‐α. These cytokines promote acquisition of sensitization, and facilitate elicitation of contact allergy via multiple mechanisms, including the recruitment of CD4+ Th1 and Th17 cells. As Th1 cells secrete large amounts of DAMPs, a DAMP immune circuit (positive‐feedback loop) is created. This is an important driver of skin sensitization and skin inflammation. Pathogenic extracellular bacteria, but not commensal bacteria, produce pathogen‐associated molecular pattern molecules, which stimulate the expression of Th1‐ and Th17‐promoting cytokines via TLR2 and TLR4. This also induces an immune circuit. The ability of the skin immune system to activate host defence mechanisms and to distinguish between pathogenic bacteria and commensals provides an explanation for why skin sensitization and ACD develop, as they are processes that rely on the same biological pathways. These pathways may also shed light on the pathogenesis of chronic pustular inflammatory dermatoses (e.g. acne vulgaris). The existence of safety signals from commensal bacteria, which prevent initiation of these pathways, may provide opportunities for novel therapeutic approaches to the treatment of inflammatory skin diseases.     

Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells

The importance of T helper 17 (Th17) cells in inflammation and autoimmunity is now being appreciated. We analyzed psoriasis skin lesions and peripheral blood for the presence of IL-17-producing T cells. We localized Th17 cells predominantly to the dermis of psoriasis skin lesions, confirmed that IL-17 mRNA increased with disease activity, and demonstrated that IL-17 mRNA expression normalized with cyclosporine therapy. IL-22 mRNA expression mirrored IL-17 and both were downregulated in parallel with keratin 16. Th17 cells are a discrete population, separate from Th1 cells (which are also in psoriasis lesions), and Th2 cells. Our findings suggest that psoriasis is a mixed Th1 and Th17 inflammatory environment. Th17 cells may be proximal regulators of psoriatic skin inflammation, and warrant further attention as therapeutic targets.     

Establishment of murine model of allergic photocontact dermatitis to ketoprofen and characterization of pathogenic T cells

BACKGROUND: Ketoprofen is well known to evoke the allergic type of photocontact dermatitis when it is applied to the skin and irradiated with ultraviolet A (UVA) light. OBJECTIVE: We aimed to establish a murine model of this photosensitivity and to characterize pathogenic T cells concerned with the sensitivity. METHODS: Various strains of mice were sensitized on two consecutive days by application of ketoprofen to the shaved abdomen and irradiation of the skin with UVA. Five days later, they were elicited with ketoprofen plus UVA on the earlobes. Immune lymph node cells and epidermal cells from the challenged sites were analyzed by RT-PCR. RESULTS: Mice were successfully sensitized and challenged with 4% and 2% ketoprofen, respective, plus UVA at 20J/cm2. The responses in H-2k mice were higher than those in the other strains examined. Immune lymph node CD4+ or CD8+ cells from ketoprofen-photosensitized H-2k mice were transferred i.v. to na?ve syngeneic recipients. Mice receiving CD4+ but not CD8+ cells exhibited ketoprofen photosensitivity, but transference of both CD4+ and CD8+ cell populations was more effective. Lymph node cells from photosensitized mice expressed high levels of mRNA for Th2 cytokine (IL-4) and Th2 chemokine receptor (CCR4) as well as Th1 cytokine (IFN-gamma) and Th1 chemokine receptor (CXCR3), as assessed by RT-PCR. In addition, epidermal cells from challenged earlobes expressed increased levels of both Th1 (TARC) and Th2 (Mig) chemokines. CONCLUSION: It is considered that not only Th1 but also Th2 cells participate in the pathogenesis of murine photocontact dermatitis to ketoprofen.     

Immunpathogenese der Psoriasis

Psoriasis is a chronic inflammatory disease of the skin and the joints. Multiple factors contribute to the initiation of psoriasis. They include specific genetic characteristics such as major histocompatibility antigens and psoriasis susceptibility genes, as well as trigger factors, namely streptococcal infections. Today, psoriasis is considered as a T‐lymphocyte mediated autoimmune disease, even though the putative autoantigen remains unknown. Bacterial proteins with similarity to structural proteins of keratinocytes are potential target antigens. As in other autoimmune diseases, inflammatory cytokines of the innate immune system initiate a cascade that activates inflammation locally in the skin, in the circulation and most likely also in lymph nodes. IFN‐γ‐producing CD4⁺ Th1‐lymphocytes seem to be of central importance in the pathogenesis of psoriasis as they critically influence differentiation and functioning of antigen presenting cells, mast cells, neutrophils and endothelial cells. This inflammatory cascade simultaneously provokes neoangiogenesis in the dermis and proliferation of keratinocytes. Based on this hypothesis, cytokines or anti‐cytokine antibodies that either inhibit T‐cell mediated inflammation or transform disease‐inducing, pro‐inflammatory Th1‐lymphocytes into a phenotype with anti‐inflammatory properties were tested in psoriasis. As both approaches improved psoriasis, they strongly support the current concept that views psoriasis as a Th1‐lymphocyte mediated disease.