寻常性银屑病皮损中SP,NK-1R和IL-23 p19基因的表达

目的探讨银屑病皮损组织中P物质(SP),SP受体(NK-1R)和IL-23 p19基因实时定量表达的意义。方法收集45例银屑病患者(PASI评分<12分的25例,PASI评分≥12分)与20名正常对照者的临床资料,采用Real-time PCR检测患者和对照组的SP,NK-1R和IL-23 p19的mRNA定量表达水平。结果SP,NK-1R和IL-23 p19mRNA在正常对照组、银屑病PASI(12组和PASI≥12组中的相对表达量均明显增高,差异有显著性(P<0.001)。相关分析显示,IL-23p19 mRNA在各组的表达与SP,NK-1R的表达呈正相关(r分别为0.867和0.846,P<0.001)。结论SP,NK-1R,IL-23p19可能参与银屑病的发病,并与银屑病严重程度相关。     

Tumor angiogenesis

In order to grow beyond minimal size and to metastasize, tumors need to induce the growth of new blood vessels (angiogenesis). Whereas in normal tissues, vascular quiescence is maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli, tumor angiogenesis is induced by increased secretion of angiogenic factors and/or by downregulation of angiogenesis inhibitors. Recent evidence suggests vascular endothelial growth factor (VEGF) as the major tumor angiogenesis factor, promoting tumor growth, invasion, and metastasis. Conversely, blocking of VEGF function inhibits angiogenesis and suppresses tumor growth in vivo. Newly identified members of the VEGF family of angiogenesis factors include placental growth factor, VEGF-B, VEGF-C, and VEGF-D, and show overlapping binding patterns to specific endothelial cell receptors. VEGF-C appears to play a major role as a lymphangiogenesis factor and as a growth factor for Kaposi's sarcoma. In contrast, endogenous inhibitors prevent blood vessel growth in normal tissues. In particular, thrombospondin-1 (TSP-1) and TSP-2 are expressed in normal skin and, when introduced into squamous cell carcinomas, potently inhibit malignant tumor growth via inhibition of tumor angiogenesis.     

寻常性银屑病皮损及非皮损中IL-23(p19/p40)和IL-12(p35/p40)mRNA的表达

目的检测寻常性银屑病患者皮损及非皮损处IL-23(p19/p40)和IL-12(p35/p40)mRNA表达,探讨其临床意义。方法采用逆转录-聚合酶链反应(RT-PCR)检测寻常性银屑病患者皮损、非皮损处及正常人皮肤中IL-23(p19/p40)和IL-12(p35/p40)mRNA的表达水平。结果寻常性银屑病患者皮损中IL-23p19及p40(IL-23/IL-12)mRNA的表达均高于非皮损组织和正常皮肤组织(P<0.05),且非皮损处高于正常对照组,差异有显著性(P<0.05);IL-12p35mRNA在银屑病皮损处、非皮损处和正常对照中表达水平差异无显著性(P>0.05)。结论在寻常性银屑病发病过程中,IL-23可能发挥较IL-12更重要的作用。     

VEGF-C及其受体在皮肤恶性黑素瘤中的表达及其临床意义

目的：研究皮肤恶性黑素瘤（MM）组织中血管内皮生长因子C（vascular endothelial growth factor-C,VEGF-C）及其受体VEGFR-3（flt-4）的表达情况,分析其在肿瘤淋巴管的生长及淋巴转移中的作用。方法：采用免疫组化SP法分析29例MM石蜡标本中VEGF-C/flt-4蛋白的表达情况,并与20例色素痣石蜡标本中VEGF-C/flt-4蛋白表达情况相对比,统计分析其与临床病理特点之间的关系。结果：VEGF-C蛋白的阳性率为96.6%（28/29）,flt-4的阳性率为86.2%（25/29）,明显高于色素痣（P〈0.01）,与肿瘤的病理分级、临床分期和肿瘤的淋巴转移显著相关（P〈0.05）;VEGF-C和flt-4的阳性表达相一致。结论：VEGF-C/flt-4在皮肤恶性黑素瘤中的表达明显高于色素痣,与肿瘤的预后密切相关,在肿瘤淋巴转移中可能有重要作用。     

IL-12 and IL-23 affect photocarcinogenesis differently

Induction of DNA damage by UVR is the key event in photocarcinogenesis. IL-12 and IL-23 are related heterodimeric cytokines consisting of a common p40 unit and a p35/IL-12 and a p19/IL-23 chain, respectively. Both exert immunomodulatory activities but are also found to reduce UVR-induced DNA damage presumably via induction of DNA repair. As both cytokines are also produced in the skin, they may mitigate the risk to develop UVR-induced skin cancer. This appears to be the case as mice lacking p40 were previously shown to be at higher risk for skin tumors upon chronic UVR exposure. As these mice express neither IL-12 nor IL-23, the individual effects of IL-12 or IL-23 could not be evaluated. Thus, mice lacking p35 (IL-12p35-/-) or p19 (IL-23p19-/-) were subjected to chronic UVR exposure. The Kaplan-Meier analysis indicated a significantly increased probability of tumor development in IL-23p19-/- but not in IL-12p35-/- mice. Taken together, in our model, loss of IL-23, but not of IL-12, enhances development of UVR-induced skin tumors, indicating that IL-23 but not IL-12 may counteract photocarcinogenesis. This may have impact on the development of future strategies utilizing antibodies against IL-12 and IL-23, respectively, for the treatment of inflammatory dermatoses.     

IL-23/Th17相关细胞因子在基底细胞癌中的表达水平及意义

目的探讨IL-23/Th17相关细胞因子在基底细胞癌(BCC)疾病进展中的作用。方法采用免疫组织化学染色的方法检测35例BCC组织及10例正常皮肤组织中IL-17、IL-22及IL-23的表达水平。结果IL-17在基底细胞癌中的表达水平高于正常皮肤组织(P<0.05),IL-17在基底细胞癌组织细胞和肿瘤间质细胞胞质中均有表达。IL-23在基底细胞癌中的表达水平高于正常皮肤组织(P<0.05),IL-23主要在基底细胞癌组织细胞胞质表达,部分位于肿瘤间质细胞胞质中。IL-22在基底细胞癌和正常皮肤组织的表达水平差异无统计学意义(P>0.05)。基底细胞癌中IL-17和IL-23的表达水平呈正相关(P<0.05)。结论IL-23/Th17相关细胞因子可能参与基底细胞癌的发生、发展。IL-23可能通过诱导Th17细胞的发育和增殖,促进IL-17分泌并在基底细胞癌的发生、发展中发挥协同作用。     

Systemic photochemotherapy decreases the expression of IFN-γ, IL-12p40 and IL-23p19 in psoriatic plaques

Psoriasis vulgaris (PV) is a chronic skin disease with unclear pathogenesis. In the present study we investigated the effect of systemic photochemotherapy (PUVA therapy- psoralen and UVA therapy) on the expression of IFN-γ, IL-12p40 and IL-23p19 in lesional psoriatic skin. Fifteen patients with chronic plaque type psoriasis selected to be treated with PUVA therapy were recruited for this study. Expression of IFN-γ, IL-12p40 and IL-23p19 in psoriatic lesions before and after twenty PUVA treatments was established by using immunohistochemistry (IHC). A significant decrease in expression (p?相似文献   

黑素瘤B16-F1体外诱导淋巴管增生的研究

目的诱导建立小鼠淋巴管内皮细胞构成的良性肿瘤模型,观察小鼠黑素瘤细胞系B16F1体外对淋巴管增生的影响。方法8周龄C57BL/6小鼠腹腔注射弗氏不完全佐剂,对诱导出的小鼠腹腔淋巴管瘤进行病理组织学观察,用免疫组化方法检测淋巴管内皮细胞标志性抗原VEGFC和Flt4。分离、分切肿物后,于纤维蛋白凝胶内用B16F1细胞条件培养液培养,倒置显微镜下观察。结果实验小鼠中膈肌腹腔面、肝脏表面及侧腹壁腹腔面可见边界清楚的散在分布白色肿瘤样组织,常规和超微病理发现为由内皮细胞构成的多管腔囊性结构,并表达淋巴管内皮细胞标志性抗原VEGFC和Flt4。倒置显微镜下可观察到从淋巴管瘤块长入纤维蛋白凝胶内的微淋巴管,B16F1细胞条件培养液可促进淋巴管的生成。结论小鼠腹腔注射弗氏不完全佐剂可稳定诱导小鼠腹腔淋巴管瘤,B16F1细胞对淋巴管的生成有促进作用,黑素瘤的转移与淋巴管生成的关系有必要进一步研究。     

Norepinephrine modulates human dendritic cell activation by altering cytokine release

Abstract:  Norepinephrine (NE) can modulate dendritic cell (DC) activation in animal models, but the response of human DC to NE and other response modifiers is as yet not completely understood. Here we report the effect of NE on the cytokine response of a mixed population of human DC cells to extracellular stimuli. These cells were obtained by differentiating human cord blood CD34+ precursor cells. NE inhibited the lipopolysaccharide (LPS)-stimulated production of interleukin (IL)-23, IL-12 p40, tumor necrosis factor (TNF)-alpha and IL-6 whereas the expression of IL-10 was not significantly affected. Thus, human cord blood-derived DC respond to NE in a manner similar to mouse Langerhans cells (LC). Furthermore, forskolin also inhibited the LPS-induced levels of TNF-alpha, IL-12 p40, IL-23 p19 and IL-6, supporting the hypothesis that the effects of NE are mediated by cAMP. Data from experiments using inhibitors of adrenergic receptors suggest that NE acts through beta-adrenergic receptors. As IL-23 promotes the differentiation of CD4+ T cells required for T_H1-mediated immunity, we suggest that NE decreases the differentiation of CD4+ T cells needed for T_H1-mediated contact hypersensitivity and that NE is a candidate regulator of human DC functions in the skin.     

Interleukin-12, interleukin-23, and psoriasis: current prospects

The clinical phenotype of psoriasis results from infiltration of T cells in the skin and elaboration of inflammatory cytokines. Interleukin (IL)-12 and, more recently, IL-23 have been implicated in the pathogenesis of psoriatic lesions. New therapies, including a monoclonal antibody against a subunit shared by IL-12 and IL-23, have been developed to treat psoriasis. Our purpose was to review the literature on IL-12 and IL-23 as a basis for understanding the use of anti-IL-12/IL-23 therapy for psoriasis. A review of English-language articles was performed using PubMed to identify articles pertaining to IL-12, IL-23, and psoriasis. IL-12 and IL-23 share a common subunit (p40) and have a distinct subunit (p35 and p19, respectively). Transgenic mice that overexpress IL-12 p40 develop inflammatory skin lesions. Both IL-12 knockout mice, which are deficient in IL-12, and human beings with a genetic IL-12 deficiency show increased susceptibility to intracellular pathogens and defective delayed-type hypersensitivity responses. These genetic deficiency states suggest the potential for adverse side effects from clinical administration of anti IL-12 p40 therapy. IL-12 p40 antibody was well tolerated in a phase I clinical trial with few adverse events and substantial improvements in psoriasis in most individuals. There was dose-dependent efficacy and substantial improvement in a larger cohort of patients in a phase II clinical trial. Larger and longer trials of anti IL-12/IL-23 therapies are needed to assess their clinical use and potential for infection and other adverse events.     

外阴阴道念珠菌病患者阴道分泌物IL-12和IL-23的检测

目的探讨细胞因子IL-12和IL-23的表达水平与不同严重程度外阴阴道念珠菌病发病的关系。方法ELISA法检测轻中度、重度各组外阴阴道念珠菌病及复发性外阴阴道念珠菌病(RVVC)患者阴道分泌物中IL-12p70和IL-23p19的表达水平,以正常女性白念珠菌携带者为对照组。结果各组外阴阴道念珠菌病患者的IL-12p70和IL-23p19表达水平均低于对照组,且各组间比较差异均有显著性(F=13.486,P=0.000:F=11.869,P=0.000);组间两两比较,重度外阴阴道念珠菌病组和RVVC组IL-12p70的水平均低于对照组,差异有显著性(t=2.243,P=0.035;t=3.397,P=0.000);RVVC组IL-23p19的水平低于对照组,差异有显著性(t=3.289,P=0.000)。结论IL-12和IL-23的表达异常可能与外阴阴道念珠菌病的发病、病情严重程度和复发有关。     

Prediction of healing in Category I pressure ulcers by skin blotting with plasminogen activator inhibitor 1, interleukin-1α, vascular endothelial growth factor C,and heat shock protein 90α: A pilot study

The prevention of progression of Category I pressure ulcers (PUs) to Category II or higher is important, as Category II or higher PUs are open wounds and have a higher infection risk. Prognosis prediction of Category I PUs is necessary to provide successful intensive care for PUs with impaired healing. We focused on skin blotting using plasminogen activator inhibitor 1 (PAI1), interleukin-1α (IL-1α), vascular endothelial growth factor C (VEGF-C), and heat shock protein 90α (HSP90α). This pilot study was conducted at long-term-care and general hospitals to examine the applicability of DESIGN-R and thermography; the feasibility of skin blotting technique; the biomarker candidates, PAI1, IL-1α, VEGF-C, and HSP90α; and sample size for prognosis prediction for Category I PUs. Patients aged >65 years underwent skin blotting, scoring for DESIGN-R, and took thermography images of their Category I PU site. Albumin signals were not detected in one out of three participants. PAI1, IL-1α, VEGF-C, and HSP90α were detected in 19 participants, among whom 11 participants could be followed up after one week. There was no difference in DESIGN-R score and skin surface temperature between normal and impaired healing groups, and the sample size was calculated as 16. In conclusion, the feasibility of skin blotting was confirmed. PAI1, IL-1α, VEGF-C, and HSP90α could be biomarker candidates for prognosis prediction for Category I PU and the combination of VEGF-C and HSP90α could be associated with the prognosis of Category I PU. We need to investigate 842 patients in a future study.     

Expression of basic fibroblast growth factor in desmoplastic melanoma

Basic fibroblast growth factor (bFGF) is an established growth factor for melanocytes and a potent angiogenic factor. The expression of bFGF was investigated in 23 desmoplastic melanomas. (DM) (12 males, median age 64 years, and 11 females, median age 54 years) by immunostaining of formalin-fixed, paraffin-embedded sections with high-affinity purified antibody raised against recombinant human bFGF (Scios Nova, Inc.). The tumors were characterized by level II invasion in 1 case (5%), level IV invasion in 11 cases (48%), level V invasion in 8 cases (35%), and indeterminate in 3 cases. bFGF expression was observed in 22 of 23 tumors (95%), either immune localized to tumor cell nuclei in 17 of 22 tumors (77%), or to the cytoplasm of tumor cells in 5 of 22 tumors (23%). Also in these cases, bFGF was strongly expressed in the nuclei of vascular endothelial cells. Maximal expression was noted in the peripheral blood vessels of 20 tumors (91%) versus intratumoral vessels of 13 DM (59%). In conclusion, the expression of predominantly nuclear bFGF by tumor cells in DM suggests a role in mediating the desmoplastic phenotype. In addition, the localization of bFGF to vascular cndothelium, particularly at the periphery of the tumor, may be relevant to tumor angiogenesis.     

Abnormal expression of interleukin-23 in mycosis fungoides/Sézary syndrome lesions

Progression of mycosis fungoides (MF) to Sézary syndrome (SS) is accompanied by a shift from a T(H)1 to a T(H)2 cytokine profile. Interleukin (IL)-23 is a novel cytokine that shares a common p40 subunit with the T(H)1 inducer, IL-12. IL-23 induces a third profile, T(H)IL-17, that is dominant in inflammation and autoimmunity. Although IL-23 induces an eczematous-like skin reaction in mice, and is expressed in T(H)1-mediated skin disorders such as psoriasis, it has not been evaluated in MF/SS. To study the role of IL-23 in MF/SS development, 40 MF/SS lesions of all stages were immunohistochemically analyzed with a novel anti-human IL-23 antibody raised against full-length human IL-23. IL-23 was detected with the catalyzed signal amplification system. The intensity and frequency of IL-23 staining were semi-quantitatively graded in both the dermal infiltrate and the epidermis. Increased expression of IL-23 was observed throughout the epidermal keratinocytes and in dermal lymphocytes compared to normal skin. IL-23 intensity did not differ significantly among the stages of MF/SS; however, in stage IVB patients, we observed lower frequency of IL-23 expression in dermal lymphocytes than in other stage patients [P = 0.13, analysis of variance (ANOVA)]. Interestingly, clusters of atypical lymphocytes, especially the epidermotropic tumor cells, demonstrated weak or absent IL-23 staining in 18 of 40 (45%) lesions. This finding was present in 4 of 5 (80%) of the stage IVB lesions and 7 of 11 (64%) of the lesions from Sézary patients. These findings indicate that abnormal IL-23 expression may play a role in the pathogenesis and progression of MF/SS.     

p53 and bcl-2 expression do not correlate with prognosis in primary cutaneous large T-cell lymphomas

Overexpression of p53 protein in cutaneous T-cell lymphoma (CTCL) has been reported in primary cutaneous large T-cell lymphomas (PCLTCL) and has been associated with tumor progression and transformation in mycosis fungoides. However, the prognostic significance of p53 expression has not been studied thus far. In the present study we investigated the expression of p53 as well as bcl-2 protein in 27 PCLTCL, including 19 CD30-positive and 8 CD30-negative lymphomas, retrieved from the registry of the Dutch Cutaneous Lymphoma Working Group.
The results were correlated with follow-up data and proliferative activity, as assessed by the percentage of MIB-1 positive tumor cells.
Overexpression of p53 protein, defined as nuclear staining of more than 5% of the tumor cells, was found in 10 of 27 cases (37%), including 6 of 19 (32%) CD30+lymphomas and 4 of 8 (50%) CD30–PCLTCL. bcl-2 protein was expressed in 6 of 19 (32%) CD30+lymphomas and in only 1 of 8 (12%) CD30–PCLTCL. However, no significant correlation between p53 or bcl-2 expression and prognosis was found, neither in the whole group, nor within the CD30+ or CD30– group. In addition, no relationship between p53 expression and proliferative activity was found. The results confirm that p53 expression is more common in PCLTCL than in mycosis fungoides and Sézary syndrome. However, neither p53 nor bcl-2 expression correlated with survival or proliferative activity.     

Abnormal expression of interleukin-23 in mycosis fungoides/Sézary syndrome lesions

Progression of mycosis fungoides (MF) to Sézary syndrome (SS) is accompanied by a shift from a T_H1 to a T_H2 cytokine profile. Interleukin (IL)-23 is a novel cytokine that shares a common p40 subunit with the T_H1 inducer, IL-12. IL-23 induces a third profile, T_HIL-17, that is dominant in inflammation and autoimmunity. Although IL-23 induces an eczematous-like skin reaction in mice, and is expressed in T_H1-mediated skin disorders such as psoriasis, it has not been evaluated in MF/SS. To study the role of IL-23 in MF/SS development, 40 MF/SS lesions of all stages were immunohistochemically analyzed with a novel anti-human IL-23 antibody raised against full-length human IL-23. IL-23 was detected with the catalyzed signal amplification system. The intensity and frequency of IL-23 staining were semi-quantitatively graded in both the dermal infiltrate and the epidermis. Increased expression of IL-23 was observed throughout the epidermal keratinocytes and in dermal lymphocytes compared to normal skin. IL-23 intensity did not differ significantly among the stages of MF/SS; however, in stage IVB patients, we observed lower frequency of IL-23 expression in dermal lymphocytes than in other stage patients [P = 0.13, analysis of variance (ANOVA)]. Interestingly, clusters of atypical lymphocytes, especially the epidermotropic tumor cells, demonstrated weak or absent IL-23 staining in 18 of 40 (45%) lesions. This finding was present in 4 of 5 (80%) of the stage IVB lesions and 7 of 11 (64%) of the lesions from Sézary patients. These findings indicate that abnormal IL-23 expression may play a role in the pathogenesis and progression of MF/SS.     

Decreased RNA expression of interleukin 17A in skin of leprosy

Interleukin-17A (IL-17A) is a proinflamatory cytokine that plays an important role in fighting pathogens at mucosal interfaces, by summoning neutrophils and upregulating cytoplasmatic antimicrobial peptides. So far, the presence of IL-17A in leprosy has not been demonstrated. The expression of IL-17A and related cytokines (IL-6 and IL-23p19) was addressed through RNA extraction and cDNA quantitative amplification in macerated biopsies of active lesions of 48?leprosy patients and 20?fragments of normal skin of individuals. Blood levels of IL-17A, IL-23p19 and IL-6 were determined by ELISA. We found an abrogated mRNA IL-17A response in all biopsies of leprosy patients, as compared with controls. Circulating IL-17A and IL-23p19 were undetectable in both patients and controls, but IL-6 was higher in lepromatous patients. Although at low levels, IL-17A mRNA in lepromatous patients had an inverse linear correlation with bacillary burden. Low expression of IL-17A in patients may be a constitutive genetic feature of leprosy patients or a circumstantial event induced by the local presence of the pathogen, as an escape mechanism.