Intraperitoneal murine Echinococcus multilocularis infection induces differentiation of TGF-β-expressing DCs that remain immature

Intraperitoneal larval infection (alveolar echinococcosis, AE) with Echinococcus multilocularis in mice impairs host immunity. Metacestode metabolites may modulate immunity putatively via dendritic cells. During murine AE, a relative increase of peritoneal DCs (pe‐DCs) in infected mice (AE‐pe‐DCs; 4% of total peritoneal cells) as compared to control mice (naïve pe‐DCs; 2%) became apparent in our study. The differentiation of AE‐pe‐DCs into TGF‐β‐expressing cells and the higher level of IL‐4 than IFN‐γ/IL‐2 mRNA expression in AE‐CD4+pe‐T cells indicated a Th2 orientation. Analysis of major accessory molecule expression on pe‐DCs from AE‐infected mice revealed that CD80 and CD86 were down‐regulated on AE‐pe‐DCs, while ICAM‐1(CD54) remained practically unchanged. Moreover, AE‐pe‐DCs had a weaker surface expression of MHC class II (Ia) molecules as compared to naïve pe‐DCs. The gene expression level of molecules involved in MHC class II (Ia) synthesis and formation of MHC class II (Ia)–peptide complexes were down‐regulated. In addition, metacestodes excreted/secreted (E/S) or vesicle‐fluid (V/F) antigens were found to alter MHC class II molecule expression on the surface of BMDCs. Finally, conversely to naïve pe‐DCs, an increasing number of AE‐pe‐DCs down‐regulated Con A‐induced proliferation of naïve CD4+pe‐T cells. These findings altogether suggested that TGF‐β‐expressing immature AE‐pe‐DCs might play a significant role in the generation of a regulatory immune response within the peritoneal cavity of AE‐infected mice.     

ILK在非慢性排斥CAN患者移植肾组织的表达及其意义

目的 探讨非慢性排斥CAN(慢性移植肾病)患者移植肾组织中整合素连接激酶(ILK)、转化生长因子β1(TGF-β1)的表达,及与移植肾间质纤维化/肾小管萎缩(IF/TA)的关系.方法 用免疫组织化学技术和计算机真彩色图像分析系统半定量检测48例非慢性排斥CAN患者移植肾组织中ILK和TGF-β1的表达情况,分析二者间及与非慢性排斥CAN患者移植肾IF/TA病理分级之间的关系.15例正常肾组织作为对照.结果 非慢性排斥CAN各组间的移植肾组织中ILK、TGF-β1的表达比正常肾组织明显增加(P<0.01),并随IF/TA病理分级呈逐渐递增的趋势;非慢性排斥CAN移植肾组织中ILK的表达与TGF-β1呈正相关(r=0.930,P<0.01);ILK、TGF-B1表达水平分别与非慢性排斥CAN移植肾IF/TA病理分级呈正相天,(r=0.860、0.938;P<0.01);Scr与IF/TA病理分级呈正相关(r=0.790,P<0.01);ILK与SCr之间呈正相关关系(r=0.865,P<0.001).结论 ILK可能是介导TGF-β1促进非慢性排斥CAN患者移植肾细胞外基质(extra cellular matrix,ECM)异常沉积发病机制,ILK在非慢性排斥CAN患者移植肾纤维化细胞信号通路中起重要作用.     

Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant, which causes a variety of severe health effects, e.g. immunosuppression, hepatotoxicity, and carcinogenesis. The main mediator of TCDD toxicity is the arylhydrocarbon receptor (AhR), which, upon activation, translocates into the nucleus and enforces gene expression. Since most of the pleiotropic effects caused by TCDD are associated with alterations in cell growth and differentiation, the analysis of the interference of the AhR with factors controlling these cellular functions seems to be a promising target regarding the prevention and treatment of chemical-provoked diseases. Cell growth and differentiation are regulated by numerous growth factors and cytokines. These multifunctional peptides promote or inhibit cell growth and regulate differentiation and other cellular processes, depending on cell-type and developmental stage. They are involved in the regulation of a broad range of physiological processes, including immune response, hematopoiesis, neurogenesis, and tissue remodeling. The complex network of growth factors and cytokines is accurately regulated and disturbances of this system are associated with adverse health effects. The molecular mechanisms by which the AhR interferes with this signaling network are multifaceted and the physiological consequences of this cross-talk are quite enigmatic. The investigation of this complex interaction is an exciting task, especially with respect to the recently described non-genomic and/or ligand-independent activities of AhR. Therefore, we summarize the current knowledge about the interaction of the AhR with three cytokine-/growth factor-related signal transducers -- the epidermal growth factor (EGF) family, tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta (TGF-beta) -- with regard to pathophysiological findings.     

Delayed liver injury and impaired hepatocyte proliferation after carbon tetrachloride exposure in BPOZ2-deficient mice

BPOZ2 is a tumor suppressive mediator in PTEN signaling pathway and plays an important role in cell proliferation. In this study, we investigated the physiology functions of BPOZ2 in CCl₄-induced liver injury and hepatocyte proliferation afterwards. After acute CCl₄ administration, BPOZ2 null mice exhibited delayed liver injury and impaired hepatocyte proliferation, which was accompanied by altered kinetics of CYP2E1 protein expression, compromised cyclin D1 expression and shortened duration of ERK activation. These results for the first time define that BPOZ2 is an important regulator involved in the injury and repair process induced by acute CC1₄ administration in mouse liver.     

阿托伐他汀对TGF-β1诱导的大鼠肺成纤维细胞分化的影响

【目的】观察阿托伐他汀对肺纤维化大鼠的肺成纤维细胞增殖的影响及其对TGF-β1诱导的大鼠肺成纤维细胞表型分化的影响。【方法】建立Wistar大鼠肺纤维化模型,1周后取肺组织进行成纤维细胞原代培养,细胞经鉴定后以不同浓度的阿托伐他汀对试验组细胞进行干预,采用MTT法测定细胞增殖情况;TGF-β1诱导细胞分化,同时给予不同浓度阿托伐他汀干预,免疫细胞化学染色（SP）法检测药物对肌成纤维标志物-αSMA表达的影响。【结果】MTT结果显示：各剂量组中不同干预天数所测得的OD值之间存在显著差异（P〈0.01）。各时间点所测OD值与不同用药物剂量之间存在交互作用（P〈0.01）。各剂量组对细胞的抑制作用之间存在显著差别（P〈0.01）。免疫细胞化学染色结果显示：药物因素对-αSMA的表达量有影响（P〈0.01）,区组因素对-αSMA的表达量有影响（P〈0.01）。【结论】阿托伐他汀可抑制肺纤维化大鼠肺成纤维细胞的增殖,同时可抑制TGF-β1诱导的成纤维细胞的分化,这主要表现在抑制细胞增殖、改变其形态、减少肌成纤维细胞的标志性产物-αSMA的产生上。     

Membrane protein GARP is a receptor for latent TGF‐β on the surface of activated human Treg

Human Treg and Th clones secrete the latent form of TGF‐β, in which the mature TGF‐β protein is bound to the latency‐associated peptide (LAP), and is thereby prevented from binding to the TGF‐β receptor. We previously showed that upon TCR stimulation, human Treg clones but not Th clones produce active TGF‐β and bear LAP on their surface. Here, we show that latent TGF‐β, i.e. both LAP and mature TGF‐β, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. Membrane localization of latent TGF‐β mediated by binding to GARP may be necessary for the ability of Treg to activate TGF‐β upon TCR stimulation. However, it is not sufficient as lentiviral‐mediated expression of GARP in human Th cells induces binding of latent TGF‐β to the cell surface, but does not result in the production of active TGF‐β upon stimulation of these Th cells.     

TGF‐β indirectly favors the development of human Th17 cells by inhibiting Th1 cells

Human Th17 clones and circulating Th17 cells showed lower susceptibility to the anti‐proliferative effect of TGF‐β than Th1 and Th2 clones or circulating Th1‐oriented T cells, respectively. Accordingly, human Th17 cells exhibited lower expression of clusterin, and higher Bcl‐2 expression and reduced apoptosis in the presence of TGF‐β, in comparison with Th1 cells. Umbilical cord blood naïve CD161⁺CD4⁺ T cells, which contain the precursors of human Th17 cells, differentiated into IL‐17A‐producing cells only in response to IL‐1β plus IL‐23, even in serum‐free cultures. TGF‐β had no effect on constitutive RORγt expression by umbilical cord blood CD161⁺ T cells but it increased the relative proportions of CD161⁺ T cells differentiating into Th17 cells in response to IL‐1β plus IL‐23, whereas under the same conditions it inhibited both T‐bet expression and Th1 development. These data suggest that TGF‐β is not critical for the differentiation of human Th17 cells, but indirectly favors their expansion because Th17 cells are poorly susceptible to its suppressive effects.