精原干细胞龛境调控因子的研究进展

精原干细胞(SSCs)龛境的稳态是通过几种信号通路和调控因子的相互作用来维持的。这些调控因子由位于生精上皮内的支持细胞和位于曲细精管之间的间质细胞分泌,其中包括胶质细胞源性神经营养因子(GDNF),成纤维细胞生长因子(FGF2),集落刺激因子-1(CSF1),WNT家族蛋白和视黄酸(RA)等,对SSCs自我更新和维持至关重要。SSCs的命运(即自我更新或分化的决定)取决于其龛境内各种因子的复杂相互作用,尽管这些因子的作用已引起广泛的研究,但我们对其表达调控的理解仍然有限。本综述的目的是讨论这些因子怎样在支持细胞中表达和在微环境中被调节,以及这些机制如何影响生殖细胞龛境的稳态。     

隐性梅毒患者血清白介素-12检测及其临床意义

白介素(IL)-12义称自然杀伤(NK)细胞刺激因子或细胞毒淋巴细胞成熟因子,它来源于B淋巴细胞．单核-巨噬细胞及抗原提呈细胞(APC),具有多种生物学功能,主要包括：诱导外周血细胞、T细胞、NK细胞产生γ—干扰素(IFN—γ）,增强NK细胞、T细胞介导的细胞毒活性,促进Th1型细胞反应,IL—12在介导感染性疾病细胞免疫中的重要作用正在成为研究热点笔者应用酶联免疫吸附试验(ELISA)检测隐性梅毒患者驱梅治疗前后血清IL～12水平的变化情况,现将结果报告如下。     

皮肤真菌病人外周血单个核细胞对毛癣菌素刺激产生的细胞因子

迟发超(?)反应是宿主防御皮肤真菌感染的重要组成部分,它与T细胞来源的细胞因子有关,其中γ-干扰素(IFN-γ)是迟发超敏反应效应阶段的一个主要因子,其它细胞因子如白介素-2(IL-2)和粒细胞巨噬细胞集落刺激因子((GM-CSF)也参与迟发型超敏反应。本研究检测了皮肤真菌感染患者的外周血单个核细胞对毛癣菌素刺激所产生的细胞因子,并讨论了与消除皮肤真菌有关的细胞因子。     

外周血及蜕膜组织中CD4~+ CD25~+调节性T细胞比例和炎症因子原因不明复发性流产的关系研究

目的:探究外周血及蜕膜组织中CD4~+CD25~+调节性T细胞比例以及相关炎症因子对原因不明复发性流产的影响。方法:选取2014年5月至2015年5月就诊于我院门诊的原因不明复发性流产(URSA)患者90例为观察组,并选取同期在妇产科门诊手术室的行人工流产手术的正常患者90例为对照组;分析两组患者的一般资料、外周血及蜕膜组织中CD4~+CD25~+调节性T细胞比例、调节性T细胞特异调节因子Foxp3和EBi3的表达以及血清炎症因子(包括TNF-α、IL-2、IL-6、IL-10)水平,研究其相关性。结果:与正常妊娠组相比,反复流产组外周血及蜕膜组织中Treg细胞比例明显降低,Foxp3和EBi3因子mRNA的表达水平明显降低,且无论URSA患者或者是正常对照组,蜕膜中各因子的表达均高于外周血中的表达,外周血TNF-α、IL-2水平明显升高,而IL-6和IL-10水平要明显降低,差异有统计学意义(P0.05)。结论:蜕膜中各因子的表达均高于外周血中的表达提示妊娠过程的主要免疫反应部位是"母-胎界面",Treg细胞比例、Treg细胞因子和Th2型因子IL-6、IL-10水平可能参与妊娠的维持,调控"母-胎界面"局部免疫耐受。对于复发性流产的发病过程具有一定的影响作用。     

系统性红斑狼疮中白细胞介素-2的改变及机理

白细胞介素-2(IL-2),原名T细胞生长因子,是一种由T淋巴细胞产生的免疫调节因子,有广谱的免疫增强活性:它能(1)维持细胞毒性T细胞系和辅助性T细胞系等在体外培养中持续增殖;能增强胸腺细胞和T细胞对有丝分裂原的增殖应答;(2)     

转录因子T-bet/GATA3与银屑病相关性研究

目的探讨外周血单一核细胞转录因子T-bet/GATA3水平与不同类型银屑病的发生及其病情的相关性。方法用RT-PCR技术检测32例银屑病患者外周血单一核细胞转录因子T-bet/GATA3 mRNA的表达,并以15例正常人作为对照组。结果银屑病患者外周血单一核细胞T-bet水平较正常人显著升高(P<0.05),进行期GATA3的水平明显降低(P<0.05)。结论T-bet/GATA3参与了银屑病发病过程。     

蜕皮甾酮抑制肿瘤坏死因子α诱导的HaCaT细胞的炎症因子的产生

目的蜕皮甾酮(Ecdysterone,EDS)是来源于中药牛膝的一类甾酮类化合物。笔者检测了蜕皮甾酮对肿瘤坏死因子(TNF)-α刺激后HaCaT角质形成细胞的炎症因子产生的影响及相关可能机制。方法采用CCK-8细胞活力测定法检测了蜕皮甾酮对细胞增殖的影响,研究蜕采用酶联免疫吸附试验(ELISA)检测了蜕皮甾酮对TNF-α刺激后HaCaT炎症因子产生的影响;采用Western印迹法对NF-κB通路和MAPK通路的相关蛋白进行了检测;采用免疫荧光法检测了TNF-α刺激后HaCaT细胞核因子(NF)-κB蛋白核转位。结果在所选浓度内,蜕皮甾酮对HaCaT细胞增殖无明显影响;蜕皮甾酮抑制了TNF-α诱导的HaCaT细胞胸腺和活化调节趋化因子(TARC),人巨噬细胞来源的趋化因子(MDC/CCL22),调节激活正常T-细胞表达分泌因子(RANTES/CCL5),白细胞介素(IL)-8的表达。蜕皮甾酮能剂量依赖性降低TNF-α诱导的HaCaT细胞胞核内P65的水平,抑制P65和核转位,提高胞浆内IκB的水平;蜕皮甾酮能剂量依赖性抑制TNF-α诱导的HaCaT细胞MAPK通路中P38,ERK,JNK蛋白的磷酸化。结论蜕皮甾酮可能通过调节NF-κB通路和MAPK通路的活化抑制了TNF-α刺激后HaCaT炎症因子产生。这为蜕皮甾酮应用于炎症性皮肤疾病提供了一定的依据。     

梅毒血清固定患者外周血调节性T细胞和Th17细胞相关因子研究

目的:检测梅毒血清固定患者外周血调节性T细胞(regulatory T cells,Treg)与Th17细胞的特异性转录因子及相关细胞因子mRNA水平的变化,初步探讨其在梅毒血清固定现象中的作用。方法:梅毒血清固定患者28例,同时以26例健康体检者作为对照组。采用实时定量方法检测外周血单个核细胞(peripheral blood mononuclear cells,PBMC)中Treg和Th17细胞特异性转录因子及相关细胞因子叉状头转录因子(FOX)P3、细胞毒性T淋巴细胞抗原(CTLA)-4、白介素(IL)-10、转化生长因子(TGF)-β和孤独核受体(ROR)γt、IL-17 mRNA的表达。结果:梅毒血清固定患者外周血FOXP3、CTLA-4、IL-10、TGF-βmRNA水平的表达量明显高于正常对照组(P0.05),RORγt和IL-17的mRNA水平表达量明显低于正常对照组(P0.05),FOXP3/RORγt mRNA水平比值明显低于对照组(P0.05)。结论:Treg与Th17细胞特异性转录因子及相关细胞因子mRNA水平的表达异常可能在梅毒血清固定现象形成中发挥重要作用。     

人类疱疹病毒-2对HaCaT细胞表达GCSF和GMCSF的影响

目的探讨HaCaT细胞在人类疱疹病毒-2(HSV-2)刺激前后粒细胞集落刺激因子(GCSF)和粒/巨噬细胞集落刺激因子(GMCSF)的表达变化及意义。方法以VERO细胞进行HSV-2扩增,采用RT-PCR和荧光实时定量PCR检测HSV-2感染HaCaT细胞前及感染后24h、48h、72h时GCSF和GMCSF的表达量。结果HaCaT细胞可自分泌GCSF和GMCSF;HSV-2感染后24h,HaCaT细胞表达GCSF及GMCSF的水平增高,72h时又明显上升,且实验组与对照组相比两种细胞因子的表达有显著性差异。结论HaCaT细胞可以自发表达GCSF和GMCSF;HSV-2刺激对HaCaT细胞表达GCSF和GMCSF有促进作用。     

炎症性皮肤病中浸润细胞的粘附分子的不同表达

粘附分子(AM)与正常皮肤的自身稳定性有关,也与皮肤病病因有关。AM 由β_1整合因子、β_2整合因子及选择因子组成。β_1整合因子也称极迟激活的抗原(VLA),因为在体外经抗原刺激后2～4周在淋巴细胞上才有VLA-1及 VLA-2出现,但也有一些 VLA 分子在非激活的白细胞和非造血细胞上表达。诱导 VLA 的表达可影响血管外白细胞的迁移。淋巴细胞相关功能抗原1(LFA-1)是β_2整合因子的一个成员,与细胞间粘附分子1(ICAM-1)相互作用,ICAM-1可在各种细胞     

TWEAK/Fn14 activation induces keratinocyte proliferation under psoriatic inflammation

Tumor necrosis factor (TNF)‐like weak inducer of apoptosis (TWEAK) has been reported to induce keratinocyte apoptosis in vitro by engaging its sole receptor of fibroblast growth factor‐inducible 14 (Fn14). In this study, we explored the role of TWEAK/Fn14 pathway in the growth of psoriatic keratinocytes that is, however, characterized by suppressed apoptotic cell death. Skin tissues from the patients with psoriasis or healthy donors were determined for TWEAK and Fn14 expression, and primary keratinocytes were evaluated under the stimulation of psoriatic proinflammatory cytokines or plus TWEAK. The results showed that both TWEAK and Fn14 were highly expressed in psoriatic skins. Moreover, the stimulation of psoriatic cytokines enhanced Fn14 expression by keratinocytes in vitro, which expressed TNF receptor 2 predominantly and proliferated increasingly with the addition of TWEAK. Furthermore, TWEAK stimulation enhanced the synthesis of survivin, inhibitor of apoptosis protein 2 and cellular FLICE‐inhibitory protein in lesional keratinocytes. Therefore, TWEAK/Fn14 interaction prefers to enhance proliferation but not apoptosis of keratinocytes under psoriatic inflammation. The activation of nuclear factor‐κB signalling‐dependent anti‐apoptotic proteins and biased expression of TNF receptors may be responsible for such a novel principle in keratinocytes under psoriatic inflammation.     

TWEAK/Fn14信号在皮肤病诊断与治疗中的作用

肿瘤坏死因子样细胞弱凋亡因子(TWEAK)属于肿瘤坏死因子配体超家族成员,通过激活其受体成纤维细胞生长诱导因子14(Fn14)而发挥多种生物学功能。TWEAK/Fn14信号的激活可以调控细胞增殖、分化过程,促进纤维增生反应、血管形成和炎症反应,参与红斑狼疮、银屑病、皮肤肿瘤等疾病的发病过程。TWEAK在某些皮肤病患者的血清及尿液中表达上调,有潜力成为早期诊断及活动度评估的生物学标志物。适度激活TWEAK/Fn14信号可促进皮肤创伤愈合,但过强或延长激活该信号则会导致各种病理性组织损害,故激活或阻断该信号的特定环节有望成为治疗皮肤病的新策略。本文综述了TWEAK/Fn14信号在皮肤病发病机制中的作用,探讨该信号在相关诊断与治疗中的潜在价值。     

Induction of RANTES by TWEAK/Fn14 interaction in human keratinocytes

TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) family, is a multifunctional cytokine that regulate cellular proliferation, angiogenesis, inflammation, and apoptosis. In this study, we investigated the effect of TWEAK on human keratinocytes. Primary cultured normal human keratinocytes constitutively expressed a TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), and produced regulated on activation, normal T expressed and secreted (RANTES) upon TWEAK stimulation in a concentration-dependent manner. The TWEAK-induced RANTES production was abrogated by anti-Fn14 antibody, and synergistically augmented by simultaneous stimulation with transforming growth factor-beta. In addition, human keratinocytes differentiated in vitro with high Ca(2+)-containing medium showed enhanced production of RANTES upon TWEAK stimulation. Furthermore, TWEAK induced rapid phosphorylation of IkappaB-alpha in human keratinocytes. Collectively, TWEAK acts on human keratinocytes as an inducer of RANTES via Fn14. Because RANTES has been implicated in inflammation, TWEAK/Fn14 interaction in human keratinocytes may be involved in the pathophysiology of inflammatory skin disorders.     

TWEAK/Fn14信号在皮肤急性创伤愈合中的作用

皮肤创伤愈合由炎症、增生和重塑等几个连续且相互重叠的阶段组成,涉及多种细胞类型、细胞因子与细胞外基质间复杂的相互作用。肿瘤坏死因子样细胞凋亡弱诱导剂(tumor necrosis factor-like weak inducer of apoptosis,TWEAK)通过与其受体成纤维细胞生长诱导因子14(fibroblast growth factor-inducible 14,Fn14)结合促进炎症反应、调控细胞增殖、迁移、分化和血管形成,从而在皮肤创伤愈合中发挥作用。本文旨在回顾皮肤创伤愈合和TWEAK/Fn14信号通路方面的研究进展,探索TWEAK/Fn14信号在急性皮肤创伤愈合中的重要作用。     

Expression of TWEAK in normal human skin, dermatitis and epidermal neoplasms: association with proliferation and differentiation of keratinocytes

Background: Tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of various inflammatory pathologies and cancer. We aimed to investigate its expression in normal human skin, inflammatory skin diseases and epidermal neoplasms. Methods: Immunohistochemistry for TWEAK was performed in samples of healthy skin, plaque psoriasis, lichen planus, prurigo nodularis, discoid lupus erythematosus, lichen sclerosus, seborrheic keratosis, common warts, actinic keratosis, Bowen's disease, keratoacanthoma and basal and squamous cell carcinoma. Double immunofluorescence was used to investigate co‐localization of TWEAK with cytokeratin‐10 and proliferating cell nuclear antigen (PCNA). Results: TWEAK was robustly expressed in the epidermis of healthy skin and decreased in inflammatory conditions, both in the context of epidermal hyperplasia and atrophy. Decreased TWEAK immunoreactivity was regularly observed in common warts, actinic keratosis and Bowen's disease, particularly in areas of marked proliferation as evidenced by PCNA‐positive nuclei. In squamous cell carcinoma, expression of TWEAK ranged from strong to completely absent, and it mostly corresponded with the expression of cytokeratin‐10. TWEAK was absent in keratoacanthoma and basal cell carcinoma. Conclusions: TWEAK is a constitutively expressed epidermal protein whose downregulation might be an early indicator of disturbed differentiation or pathologic proliferation of keratinocytes that accompany inflammatory and neoplastic skin diseases. Peternel S, Manestar‐Bla?i? T, Brajac I, Prpi?‐Massari L, Ka?telan M. Expression of TWEAK in normal human skin, dermatitis and epidermal neoplasms: association with proliferation and differentiation of keratinocytes.     

Tumor necrosis factor‐like weak inducer of apoptosis and its receptor fibroblast growth factor‐inducible 14 are expressed in urticarial vasculitis

Tumor necrosis factor (TNF)‐like weak inducer of apoptosis (TWEAK), a member of the TNF family, has been implicated as a pro‐inflammatory cytokine in many types of autoimmune and infectious diseases. However, information about TWEAK in dermatological diseases is limited. To date, no studies have investigated the roles of TWEAK in patients with urticarial vasculitis (UV). This study aimed to assess serum TWEAK levels, together with TWEAK and fibroblast growth factor‐inducible 14 (Fn14) expressions of skin lesions in patients with UV. Serum TWEAK levels in patients with UV, together with patients with cutaneous leukocytoclastic angiitis (CLA) and healthy controls were detected by enzyme‐linked immunosorbent assay; TWEAK and Fn14 expressions of skin lesions were analyzed by immunohistochemistry. Results showed that TWEAK and Fn14 were abundantly expressed in the dermal vessel wall of lesional skin in patients with UV but not healthy controls. Serum TWEAK levels in the acute stage in patients with UV were significantly higher than those in the convalescent stage and healthy controls. Serum TWEAK levels were elevated significantly in patients with CLA compared with those in healthy controls. Our previous study indicated that TWEAK may be an important mediator for the development of vascular inflammation in skin. In addition, we also found that TWEAK blockade substantially reduced vascular damage and perivascular leukocyte infiltrates in lipopolysaccharide‐induced cutaneous vasculitis. Our study shows that TWEAK may be associated with the pathogenesis of UV; it is therefore suggested that TWEAK may be a potential therapeutic target for UV and other types of cutaneous vasculitis.     

IL-22在银屑病发病机制中的作用

研究显示,白介素22能促进上皮细胞产生异常炎症介质.白介素22是一种重要的细胞因子,主要由Th17细胞产生,参与炎性细胞浸润,细胞增殖,细胞迁移及防御作用等.在银屑病皮损中,白介素22水平升高,其通过与角质形成细胞表面白介素22受体结合,导致细胞因子和炎症介质改变,起到趋化炎性细胞,促角质形成细胞增殖,抑制角质形成细胞分化的作用,是银屑病发病中重要的细胞因子.介绍银屑病皮疹中白介素22促进炎症细胞浸润和角质化细胞增殖的作用,以及银屑病中角质形成细胞活化产物的变化并通过白介素22治疗银屑病的疗效应证实其作用.

Abstract：

Studies have shown that IL-22 could promote epithelial cells to produce abnormal inflammatory mediators.IL-22 is an important cytokine mainly produced by Th17 cells and participates in inflammatory cell infiltration, cell proliferation, migration, defense, and so on.In psoriatic lesions, the expression level of IL-22 is elevated.By binding to its receptor on the surface of keratinocytes, IL-22 can alter the expressions of cytokines and inflammatory mediators, induce the chemotaxis of inflammatory cells, promote the proliferation and inhibit the differentiation of keratinocytes.Therefore, IL-22 is an important cytokine in the pathogenesis of pasoriasis.This paper describes the upregulatory effect of IL-22 on inflammatory cell infiltration and keratinocyte proliferation, alterations in products of activated keratinocytes in psoriasis, as well as the role of IL-22 in the pathogenesis of psoriasis which has been evidenced by the therapeutic effect of IL-22 on psoriasis.     

Peroxisome Proliferator-Activated Receptors (PPARs) and the Human Skin

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate lipid, glucose, and amino acid metabolism. More recently, PPARs and corresponding ligands have been shown in skin and other organs to regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. These new functions identify PPARs and corresponding ligands as potential targets for the treatment of various skin diseases and other disorders. It has been shown that in inflammatory skin disorders, including hyperproliferative psoriatic epidermis and the skin of patients with atopic dermatitis, the expression of both PPARalpha and PPARgamma is decreased. This observation suggests the possibility that PPARalpha and PPARgamma activators, or compounds that positively regulate PPAR gene expression, may represent novel NSAIDs for the topical or systemic treatment of common inflammatory skin diseases such as atopic dermatitis, psoriasis, and allergic contact dermatitis. Moreover, recent findings indicate that PPAR-signaling pathways may act as a promising therapeutic target for the treatment of hyperproliferative skin diseases including skin malignancies. Studies in non-diabetic patients suggest that oral thiazolidinediones, which are synthetic ligands of PPARgamma, not only exert an antidiabetic effect but also may be beneficial for moderate chronic plaque psoriasis by suppressing proliferation and inducing differentiation of keratinocytes; furthermore, they may even induce cell growth arrest, apoptosis, and terminal differentiation in various human malignant tumors. It has been reported that PPARalpha immunoreactivity is reduced in human keratinocytes of squamous cell carcinoma (SCC) and actinic keratosis (AK), while PPARdelta appears to be upregulated. Additionally, the microvessel density is significantly higher in AK and SCC that express high levels of PPARdelta. PPARdelta has been demonstrated to have an anti-apoptotic role and to maintain survival and differentiation of epithelial cells, whereas PPARalpha and PPARgamma activators induce differentiation and inhibit proliferation and regulate apoptosis. In melanoma, the growth inhibitory effect of PPARgamma activation is independent of apoptosis and seems to occur primarily through induction of cell cycle arrest in the G1 phase of the cell cycle or induction of re-differentiation. PPARalpha activation causes inhibition of migration of melanoma cells and anchorage-independent growth, whereas primary tumor growth remains unaltered. In clinical trials of gemfibrozil, a PPARalpha ligand, significantly fewer patients treated with this lipid-lowering drug were diagnosed with melanoma as compared to those in the control group. In conclusion, an increasing body of evidence indicates that PPAR signaling pathways may represent interesting therapeutic targets for a broad variety of skin disorders, including inflammatory skin diseases such as psoriasis and atopic dermatitis, and skin malignancies.     

Resident skin cells in psoriasis: a special look at the pathogenetic functions of keratinocytes

Psoriasis is a chronic inflammatory skin disease characterized by exaggerated keratinocyte proliferation. Current paradigm indicates that psoriasis is driven by T cell–mediated immune responses targeting keratinocytes. However, psoriasis cannot be explained solely on the basis of T-cell activation, and it is likely that intrinsic alterations in epidermal keratinocytes play a very relevant role in disease expression. In particular, keratinocytes may be important in initiating, sustaining, and amplifying the inflammatory responses by expressing molecules involved in T-cell recruitment, retention, and activation. Keratinocytes are also a relevant source of growth factors for angiogenesis. Finally, intrinsic defects in cytokine and growth factor signaling in keratinocytes may be responsible for their aberrant hyperproliferation and differentiation to T cell–derived signals. Other skin resident cells such as fibroblasts, mast cells, and endothelial cells also contribute to psoriasis pathogenesis by expressing molecules involved in T-cell recruitment and activation.