Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production

Estrogen appears to play a central role in the immune response and immune-mediated diseases. Estrogen receptors are expressed in a variety of immunocompetent cells, including CD4(+) and CD8(+) T cells and macrophages. Clinical observations indicate that some autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, frequently remit during pregnancy but exacerbate, or have their onset during the postpartum period. Pharmacological levels of estrogen also appear to ameliorate certain autoimmune diseases. In addition, estrogen is known to suppress certain infectious diseases, as well as T cell-mediated responses toward oxazolone, keyhol lympet hemocyanin, Listeria soluble protein and purified protein derivatives. The immune basis for these phenomena is poorly understood. Based on a distinctive profile of cytokine production, data accumulated thus far have revealed modulatory effects for estrogen on the TH1-type and TH2-type cells, which represent two polarized forms of the effector specific immune response. Recent evidence indicates that estrogens inhibit the production of TH1 proinflammatory cytokines, such as IL-12, TNF-alpha and IFN-gamma, whereas they stimulate the production of TH2 anti-inflammatory cytokines, such as IL-10, IL-4, and TGF-beta. This can explain why estrogen suppresses and potentiates TH1- and TH2-mediated diseases, respectively. We hypothesize that exacerbation or suppression of inflammatory diseases by estrogen is mediated by skewing TH1-type to TH2-type response. This view represents a novel mechanism for the modulatory effect of estrogen on certain inflammatory diseases that can lead to beneficial or detrimental impacts depending on the type of immune involved. Such a concept is valuable when considering the application of combination therapies that include estrogen.     

健康在线

黑龙江成功完成我国首例微创溶栓手术 我国第1例利用国际最新球囊保护溶栓技术进行的微创手术,近日在黑龙江省医院获得成功。 据参与手术的专家介绍,微创溶栓手术就是利用国际最先进的微创手术方法,为下肢动静脉血栓患者,进行球囊保护溶栓手术。这一新技术主要采用带有双球囊的振动溶栓导管,在充起球囊后,启动振动装置,同时向血栓部位注入溶栓剂,通过插入血栓中的振动溶栓直线振动,仅用15分钟就彻底溶解动脉血栓。     

乌司他丁对急性肺损伤患者Th1/Th2细胞因子比率变化的影响

目的探讨乌司他丁对急性肺损伤患者Th1/Th2细胞因子比率变化的影响。方法选择急性肺损伤患者60例,随机分为常规组和乌司他丁组,每组30例,同时选择健康体检者30例为对照组。所有患者进行ApacheⅡ评分、PO2/FiO2监测,用酶联免疫吸附法测定血清Th1类细胞因子(IFN-γ)和Th2类细胞因子(IL-4)水平。结果与对照组比较,常规组和乌司他丁组血清IFN-γ、IFN-γ/IL-4明显升高(P<0.05),而IL-4水平差异无统计学意义(P>0.05);与常规组治疗后比较,乌司他丁组治疗后患者血清IFN-γ、IFN-γ/IL-4明显下降(P<0.05),IL-4水平差异无统计学意义(P>0.05)。结论急性肺损伤患者Th1/Th2类细胞因子失衡,乌司他丁可以调节炎性细胞因子的释放,恢复Th1/Th2类细胞因子的平衡,发挥肺保护作用。     

复方TH抗肿瘤作用研究

目的研究复方TH体内外抗肿瘤活性,筛选抗肿瘤新复方。方法体外采用噻唑蓝（MTT）法检测复方TH对体外培养的人肺癌细胞A549、人食管癌细胞EC9706、人结肠癌细胞LoVo、人肝癌细胞Hep G2、人乳腺癌细胞MCF 7的生长抑制作用,计算生长抑制率及半数抑制浓度（IC50）。将小鼠接种肝癌H22细胞后随机分成5组：空白对照组（双蒸水）、阳性对照组（顺铂0.005 g&#8226;kg 1）、3个剂量复方TH给药组（0.030,0.060,0.090 g&#8226;kg 1）,复方TH组次日开始灌胃给药0.3 mL,连续8 d。每间隔1 d每只小鼠腹腔注射给药0.2 mL,共3次。末次给药后24 h处死小鼠,计算肿瘤抑制率、胸腺指数、脾脏指数。结果复方TH可以显著抑制人肺癌细胞A549、人食管癌细胞EC9706、人结肠癌细胞LoVo、人肝癌细胞Hep G2、人乳腺癌细胞MCF 7的生长,IC50分别为7.15,5.41,2.49,2.18和1.37 μg&#8226;mL 1;TH复方小、中、高剂量组的肿瘤抑制率分别为52.8%,44.9%和47.9%;与对照组比较均差异有极显著性（均P＜0.01）,脏器指数及质量与对照组比较均差异无显著性,与阳性对照组比较差异有极显著性（P＜0.01）。结论复方TH对体外培养的肿瘤细胞有较强的细胞毒性作用,可显著抑制细胞生长;体内可以明显抑制实体瘤生长。     

Immunomodulatory effect of Astragali Radix extract on murine TH1/TH2 cell lineage development

Astragali Radix (AR), is a popular herbal medicine used to treat allergic diseases in Korea, Japan and China. Our study examined the effect of an AR ethanol extract on both in vitro and in vivo murine CD4 T cells' differentiation into Th1 and Th2 subsets. CD4 T cells from Balb/c mice were activated with anti-CD3/anti-CD28 mAb in the presence of AR for 2 d. AR treated cells showed an elevated level of IL-4 but a reduced level of IFN-gamma secretion. In addition, in vitro Th1/Th2 polarization experiments revealed that AR enhanced the levels of IL-4 in Th2 cells but reduced the levels of IFN-gamma in Th1 cells. To elucidate the effects of AR in Th1/Th2 lineage development during the in vivo condition, AR was administrated orally to BALB/c mice. The results demonstrated that AR administration significantly increased IL-4 production in both the serum and supernatant of splenocyte culture, while IFN-gamma secretion was diminished upon in vivo activation with anti-CD3 antibody. Our data clearly indicates that AR selectively alters Th1/Th2 cytokine secretion patterns and provides the pharmacological basis for AR's clinical applications.     

甘草对慢性小鼠哮喘模型气道炎症及外周血Th1/Th2失衡的影响

目的：探讨甘草对慢性小鼠哮喘模型气道炎症及外周血，Th1／Th2失衡的影响。方法：用卵蛋白致敏建立慢性小鼠哮喘模型，观察甘草对肺组织形态学影响，用ELISA法检测外周血肿瘤坏死因子-γ（IFN-γ）和白介素-4（IL-4）的水平变化。结果：与哮喘组小鼠相比较，甘草治疗后小鼠肺组织的炎症病理变化减轻，血清IFN-γ水平升高，IL-4水平降低。结论：甘草能有效抑制慢性哮喘产生的气道炎症，具有调节免疫平衡作用。     

中药有效成分Vam3对小鼠气道非特异性炎症模型T_H1/T_H2应答的调节作用

本研究的目的是利用气道炎症小鼠模型来探讨中药有效成分Vam3调节气管炎症的免疫平衡的效果。小鼠用伴清蛋白腹膜内致敏,然后气管内发敏。在首次发敏后24h用中药有效成分Vam3进行治疗。用地塞米松治疗组、生理盐水组及不作处理的空白对照组作为对照。中药有效成分Vam3的评价主要是对抗原特异性抗体的产生及产生细胞因子类型的影响。结果显示,与盐水对照组相比,中药有效成分Vam3可有效减少抗原特异性IgE、IL-4、IL-5和IL-13的水平,而IgG2和IFN-γ合成不受抑制。证实其有抗气道炎症和调节TH1/TH2应答类型的作用,可用于气道炎症的治疗。     

5TH SOUTHEAST ASIAN AND WESTERN PACIFIC REGIONAL MEETING OF PHARMACOLOGISTS (5TH SEA/WP RMP)

The 5th SEA/WP RMP will be held in July 4～8,1988 in Beijing, China. The following is its first announcement and call for papers.Dear Colleagues:     

地塞米松与吡格列酮对哮喘T_H1/T_H2细胞因子作用机制的比较

目的初步探讨地塞米松(DXM)和过氧化物酶增殖活化受体γ(PPARγ)激动剂吡格列酮对哮喘模型TH1/TH2细胞因子表达的影响及其机制,并比较二者的异同。方法24只Balb/c小鼠随机分为正常对照组、哮喘组、地塞米松组和吡格列酮组,每组各6只。采用W estern b lot方法检测各组小鼠肺组织T-bet和GATA3的表达,同时运用流式细胞仪检测小鼠脾细胞胞内白介素4(IL-4)和干扰素γ(IFNγ)的表达。结果哮喘模型鼠脾细胞内IL-4/IFNγ比值与正常组相比明显升高(P<0.01),经DXM治疗后,IL-4/IFNγ比值明显降低,肺组织GATA 3和T-bet的表达均减低(P<0.01),但GATA 3比T-bet减低更明显;而经吡格列酮治疗后,不仅IL-4/IFNγ比值明显降低(P<0.01),同时肺组织T-bet的表达也明显增高(P<0.01),但GATA3无变化(P>0.05)。结论地塞米松与吡格列酮对哮喘TH1/TH2细胞因子的调节及机制有所不同,地塞米松同时抑制GATA3和T-bet的表达,从而扭转了IL-4和IFNγ的比值;而吡格列酮可能通过参与调控TH1细胞转化过程中重要转录因子T-bet的表达,改变IL-4/IFNγ比值,从而改善相应的炎性症状。     

Effects of bisphenol A on antigen-specific antibody production,proliferative responses of lymphoid cells,and TH1 and TH2 immune responses in mice

1. We investigated the effect of bisphenol A (BPA), which binds estrogen receptors, on immune responses including production of antigen-specific antibodies, proliferative responses of lymphoid cells, and Th1 and Th2 responses. 2. For this investigation, mice were p.o. given varying doses including 3, 30, 300, and 3000 micro g kg(-1) of BPA immediately after immunization with hen egg lysozyme (HEL) (day 0) and then daily by day 20. On day 21, anti-HEL IgG antibodies in sera and proliferative responses of spleen cells to the antigen were measured. Anti-HEL IgG2a antibodies and IFN-gamma secreted from splenic lymphocytes were also measured as indicators of Th1 immune responses, while anti-HEL IgG1 antibodies and IL-4, as those of Th2 responses. 3. The results showed that treatment with 3000 micro g kg(-1) of BPA was followed by a significant increase in anti-HEL IgG as well as the antigen-specific cell proliferation. Anti-HEL IgG2a production and IFN-gamma secretion were significantly enhanced in mice treated with 300 and 30 micro g kg(-1) of BPA, respectively, while anti-HEL IgG1 production and IL-4 secretion were augmented in animals given 3000 and 300 micro g kg(-1) of the chemical, respectively. 4. Augmentation of these immune responses was also observed in mice exposed to 0.3-30 micro g kg(-1) of estradiol, although Th1 responses appeared to be more sensitive to the sex hormone than Th2 responses. 5. These results suggest that BPA may play a role in augmenting immune responses, especially Th1 responses.     

CD4+ T cell depletion changes the cytokine environment from a TH1/TH2 response to a TC17-like response in a murine model of atopic dermatitis

Atopic dermatitis (AD) is a common inflammatory skin disease often associated with co-morbidities including allergic hypersensitivity. We have studied induced AD-like disease in NC/Nga mice using the hapten FITC. Following FITC-treatment the NC/Nga mice develop AD-like skin lesions in regard to the histopathological and immunological changes. Consistent with AD in humans the number of CD4(+) T cells within the blood and draining lymph nodes increases considerably. To evaluate the contribution of T(H) cells on disease development we examined the effect of CD4 depletion. Following CD4 depletion the mice still develop AD-like skin lesions characterized by e.g. increased epidermal proliferation, hyperkeratosis and cellular infiltrate, however, the underlying immunological mechanisms change. CD4 depletion results in increased IL-17A and IL-22 production, which traditionally are associated with T(H)17 cells. Using confocal microscopy, we demonstrate that epidermal CD8(+) cells are positive for IL-17A, indicating that these cells are T(C)17 cells, the cytotoxic T cell counterpart to T(H)17 cells. In conclusion, we show that NC/Nga mice develop AD-like disease following CD4 depletion. This is mirrored by an increased production of IL-17A, which we suggest are produced by T(C)17 cells. These findings support that CD8(+) T cells can play a role in AD.     

TH17 is involved in the remarkable regression of metastatic malignant melanoma to topical diphencyprone

The authors provide an update on a previously reported patient with in-transit metastatic melanoma of the scalp treated with topical diphencyprone (DPCP). Molecular studies implicate the thymus-derived TH17 lymphocyte subset in a remarkable immunotherapeutic regression. The authors performed RT-PCR of total RNA from paraffin-embedded tissue before and after treatment with DPCP. Before treatment with DPCP, the authors found elevated expression of IL 17C/D/E/F; after treatment there was no detectable expression. Conversely, increased expression of PLZF/CD27 and CTLA4 was seen after treatment with no expression before treatment. No expression of IL17A/B, CD7, RORgTand FoxP3 were before or after treatment. Conclusions are limited to only the time samples were obtained. Remarkable regression of an in-transit metastatic melanoma treated with the immunomodulatory agent DPCP showed gain and loss of gene expression of the TH17 pathway. Further study of this pathway from NK to NK-T to TH7 and TH1 cells both with and without accessory or dendritic cells will improve understanding of contact sensitizers as topical immunomodulators.     

Susanna Aleksandrovna Minina (On Her 70TH Birthday)

Anniversaries

Susanna Aleksandrovna Minina (On Her 70TH Birthday)     

Pulmonary delivery of TH9507, a growth hormone releasing factor analogue, in the dog

A modified growth hormone releasing factor (GRF; TH9507), a 44 amino acid peptide analogue of natural human growth hormone releasing factor, is being developed for the treatment of age-associated conditions resulting from diminished growth hormone (GH) secretion. The inhalation route of administration is being considered as an alternative to subcutaneous injection. A study was undertaken in dogs to investigate the absorption of TH9507 following pulmonary delivery. Male beagle dogs were administered TH9507 by intratracheal dry powder insufflation and subcutaneous injection at doses of approximately 375 and 38microg/kg, respectively. In a separate study, male and female dogs received 100microg/kg intravenously. Blood samples were collected at selected sampling times after dosing and plasma levels of TH9507 were measured by radioimmunoassay. The bioavailability by the inhaled route was 41% relative to subcutaneous dosing, with an absolute bioavailability estimated at 13%. No significant difference was observed for the terminal half-life of TH9507 after intratracheal (39min) and subcutaneous (26min) administrations. The mean residence time (MRT) was greater following intratracheal administration (74min versus 52min; P<0.01). These data indicate that the delivery of the TH9507 by the inhalation route may provide a suitable alternative to subcutaneous injection.     

死亡素突变体TH1在裂殖酵母中的分泌表达

通过PCR方法人工合成带有K28信号肽的死亡素突变体基因，构建了重组表达载体pRHZ-41k28Th1，转化到裂殖酵母中进行表达，发酵液中检测到与TH1理论分子量一致的多肽分子，微量稀释法检验表达产物具有抑菌活性，并计算了粗产物对4种供试菌的最低抑菌浓度。     

氨茶碱对哮喘缓解期儿童TH相关细胞因子调节作用的实验研究

目的：探讨氨茶碱对哮喘缓解期患儿抗炎作用免疫机理。方法：采集20例缓解期哮喘儿童PBMCs与氨茶碱共同培养，按不同浓度（0、5、10、20mg/L）分为哮喘对照组（ACG）、处理组（ATG1）、ATG2和ATG3，同时设立正常对照组（NCG）。采用ELISA检测培养24h后各组PBMCs上清液中IL-4、IL-10、IFN-γ浓度和血清IgE浓度，同时计数外周血EOS。结果：哮喘缓解期患儿EOS和IgE水平均明显高于NCG；ACG组IL-4、IL-10明显高于NCG，IFN-γ明显低于NCG；20mg／L氨茶碱能显著抑制IL-4、IL-10分泌，提高IFN-γ的分泌，逆转IL-4/IFN-γ比值。结论：在哮喘缓解期患儿仍然存在TH2亚群功能亢进；20mg／L的氨茶碱可以通过纠正TH1和TH2细胞因子的失衡状态而发挥抗炎作用。