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1.
α1-Antitrypsin modifies general natural killer cell interactions with dendritic cells and specific interactions with islet β-cells in favour of protection from autoimmune diabetes 下载免费PDF全文
Ofer Guttman Rami Yossef Gabriella Freixo-Lima Peleg Rider Angel Porgador Eli C Lewis 《Immunology》2015,144(3):530-539
The autoimmune destruction of pancreatic β-cells is the hallmark of type 1 diabetes (T1D). Failure of anti-CD3 antibodies to provide long-lasting reversal of T1D and the expression of a natural killer (NK) cell ligand on β-cells suggest that NK cells play a role in disease pathogenesis. Indeed, killing of β-cells by NK cells has been shown to occur, mediated by activation of the NK cell activating receptor, NKp46. α1-Antitrypsin (AAT), an anti-inflammatory and immunomodulatory glycoprotein, protects β-cells from injurious immune responses and is currently evaluated as a therapeutic for recent onset T1D. Although isolated T lymphocytes are not inhibited by AAT, dendritic cells (DC) become tolerogenic in its presence and other innate immune cells become less inflammatory. Yet a comprehensive profile of NK cell responses in the presence of AAT has yet to be described. In the present study, we demonstrate that AAT significantly reduces NK cell degranulation against β-cells, albeit in the whole animal and not in isolated NK cell cultures. AAT-treated mice, and not isolated cultured β-cells, exhibited a marked reduction in NKp46 ligand levels on β-cells. In related experiments, AAT-treated DC exhibited reduced inducible DC-expressed interleukin-15 levels and evoked a weaker NK cell response. NK cell depletion in a T1D mouse model resulted in improved β-cell function and survival, similar to the effects observed by AAT treatment alone; nonetheless, the two approaches were non-synergistic. Our data suggest that AAT is a selective immunomodulator that retains pivotal NK cell responses, while diverting their activities away from islet β-cells. 相似文献
2.
Vestibular schwannoma (VS), the fourth most common intracranial tumor, arises from the Schwann cells of the vestibular nerve. Although several pathways have been independently implicated in VS pathobiology, interactions among these pathways have not been explored in depth. We have investigated the potential cross-talk between hepatocyte growth factor (HGF) and vascular endothelial growth factor-A (VEGF-A) in human VS, an interaction that has been described in other physiological and pathological cell types. We affirmed previous findings that VEGF-A signaling is aberrantly upregulated in VS, and established that expression of HGF and its receptor cMET is also significantly higher in sporadic VS than in healthy nerves. In primary human VS and Schwann cell cultures, we found that VEGF-A and HGF signaling pathways modulate each other. siRNAs targeting cMET decreased both cMET and VEGF-A protein levels, and siRNAs targeting VEGF-A reduced cMET expression. Additionally, siRNA-mediated knockdown of VEGF-A or cMET and pharmacologic inhibition of cMET decreased cellular proliferation in primary human VS cultures. Our data suggest cross-talk between these 2 prominent pathways in VS and highlight the HGF/cMET pathway as an additional important therapeutic target in VS. 相似文献
3.
Michael Moulin Ginnie T. D. T. Nguyen Mark A. Scaife Alison G. Smith Teresa B. Fitzpatrick 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(36):14622-14627
Thiamin (vitamin B1) is an essential micronutrient needed as a cofactor for many central metabolic enzymes. Animals must have thiamin in their diet, whereas bacteria, fungi, and plants can biosynthesize it de novo from the condensation of a thiazole and a pyrimidine moiety. Although the routes to biosynthesize these two heterocycles are not conserved in different organisms, in all cases exogenous thiamin represses expression of one or more of the biosynthetic pathway genes. One important mechanism for this control is via thiamin-pyrophosphate (TPP) riboswitches, regions of the mRNA to which TPP can bind directly, thus facilitating fine-tuning to maintain homeostasis. However, there is little information on how modulation of riboswitches affects thiamin metabolism in vivo. Here we use the green alga, Chlamydomonas reinhardtii, which regulates both thiazole and pyrimidine biosynthesis with riboswitches in the THI4 (Thiamin 4) and THIC (Thiamin C) genes, respectively, to investigate this question. Our study reveals that regulation of thiamin metabolism is not the simple dogma of negative feedback control. Specifically, balancing the provision of both of the heterocycles of TPP appears to be an important requirement. Furthermore, we show that the Chlamydomonas THIC riboswitch is controlled by hydroxymethylpyrimidine pyrophosphate, as well as TPP, but with an identical alternative splicing mechanism. Similarly, the THI4 gene is responsive to thiazole. The study not only provides insight into the plasticity of the TPP riboswitches but also shows that their maintenance is likely to be a consequence of evolutionary need as a function of the organisms’ environment and the particular pathway used. 相似文献
4.
肺功能不仅是早产儿生命的最重要的决定因素,也是影响其远期预后的重要因素。肺和肠道微生物群落结构复杂,通过肠-肺轴在肺部疾病中起着重要调控作用。本文将对以支气管肺发育不良为主的呼吸系统疾病中早产儿的肠-肺轴及其病理生理学的许多方面,并探讨现有的和创新的预防和治疗方法。 相似文献
5.
Brassinosteroids inhibit pathogen-associated molecular pattern-triggered immune signaling independent of the receptor kinase BAK1 总被引:1,自引:0,他引:1
Albrecht C Boutrot F Segonzac C Schwessinger B Gimenez-Ibanez S Chinchilla D Rathjen JP de Vries SC Zipfel C 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(1):303-308
Plants and animals use innate immunity as a first defense against pathogens, a costly yet necessary tradeoff between growth and immunity. In Arabidopsis, the regulatory leucine-rich repeat receptor-like kinase (LRR-RLK) BAK1 combines with the LRR-RLKs FLS2 and EFR in pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and the LRR-RLK BRI1 in brassinosteroid (BR)-mediated growth. Therefore, a potential tradeoff between these pathways mediated by BAK1 is often postulated. Here, we show a unidirectional inhibition of FLS2-mediated immune signaling by BR perception. Unexpectedly, this effect occurred downstream or independently of complex formation with BAK1 and associated downstream phosphorylation. Thus, BAK1 is not rate-limiting in these pathways. BRs also inhibited signaling triggered by the BAK1-independent recognition of the fungal PAMP chitin. Our results suggest a general mechanism operative in plants in which BR-mediated growth directly antagonizes innate immune signaling. 相似文献
6.
Ester Leno-Duran Raquel Mufioz-Fernfindez Enrique Garcia Olivares Irene Tirado-GonzAlez 《Cellular & molecular immunology》2014,11(5):449-455
A successful pregnancy relies on immunological adaptations that allow the fetus to grow and develop in the uterus, despite being recognized by maternal immune cells. Among several immunocompetent cell types present within the human maternal/fetal interface, DC-SIGN~ dendritic cells (DCs) and CD56+ natural killer (NK) cells are of major importance for early pregnancy maintenance, not only generating maternal immunological tolerance but also regulating stromal cell differentiation. Previous reports show the presence of NK-DC cell conjugates in first trimester human decidua, suggesting that these cells may play a role in the modulation of the local immune response within the uterus. While effective immunity is necessary to protect the mother from harmful pathogens, some form of tolerance must be activated to avoid an immune response against fetal antigens. This review article discusses current evidence concerning the functions of DC and NK cells in pregnancy and their liaison in human decidua. 相似文献
7.
8.
Hidenori Itabashi Chihaya Maesawa Hiroki Oikawa Koji Kotani Eiichi Sakurai Kuniyuki Kato Hideaki Komatsu Hiroyuki Nitta Hidenobu Kawamura Go Wakabayashi Tomoyuki Masuda 《Hepatology research》2008,38(6):601-613
Aim: The cross-talk pathway between angiotensin II (AngII) and the epidermal growth factor receptor (EGFR) mediated by epidermal growth factor (EGF)-like ligands cleaved by a disintegrin and metalloprotease (ADAM) has been elucidated in several cell types. Even though the liver is a representative angiotensinogen-producing organ, such cross-talk has never been elucidated in hepatocellular carcinomas (HCCs). We investigated whether AngII exerted a mitogenic effect on HCC cell lines through the AngII-EGFR cross-talk pathway. Methods: We determined the expression and/or phosphorylation status of AngII receptor type 1 (AGTR1), ADAM9, ADAM17, ERK1/2, STAT3, AKT and EGFR in five HCC cell lines using Western blotting. Proliferation and invasion activities were measured by ATP and Matrigel invasion assays, respectively. Results: AGTR1 was expressed ubiquitously in HCC cell lines. EGFR expression in HepG2 was relatively weaker than that in the remaining HCC cell lines. The phosphorylation status of EGFR, ERK1/2, STAT3 and AKT was upregulated by AngII treatment in two EGFR-overexpressing cell lines (Huh7 and PLC/PRF/5), but not in HepG2 (showing weak EGFR expression). AngII stimulation significantly accelerated proliferation and invasion activities in Huh7 and PLC/PRF/5, and was inhibited by pretreatment with an ADAM inhibitor. A selective AGTR1 blocker significantly repressed proliferation activity in both cell lines, but did not significantly repress the invasion activity. Both chemical agents and neutralizing antibodies against ADAMs (ADAM9 and ADAM17) and EGF-like ligands suppressed EGFR transactivation and/or subsequent phosphorylation of ERK1/2, STAT3 and AKT. Conclusion: These results suggest that AngII-EGFR cross-talk signaling mediated by ADAMs is involved in the proliferation and invasion activities of several HCC cell lines. 相似文献
9.
《International reviews of immunology》2013,32(6):443-453
Cross-talk within the innate immune pathways is highly complex and contains many unknowns. Here, we discuss the different combinations of PAMPs, together with the sequence, order, and dosage of consecutive PAMP challenges, which determine the nature of the immune response by macrophages. The engagement of different Toll-like receptor (TLR) ligands leads to quantitatively and qualitatively unique cytokine production, showing that TLR pathway crosstalk enables the innate immune system to orchestrate immediate local and global responses. It is likely that multiple pathways are involved in the regulation of cytokine synergy, including many that have yet to be discovered. 相似文献
10.
目的探讨Notch2和MEK/ERK信号通路在胃癌细胞SGC-7901中是否存在交叉作用。方法采用体外化学合成的特异性针对Notch2的siRNA(Notch2siRNA)和丝裂原激活蛋白激酶(MEK)/细胞外信号调节激酶(ERK)信号通路的抑制剂PD98059,分别单独和联合处理体外培养的胃癌SGC-7901细胞,以转染阴性对照siRNA(control siRNA)细胞作为siRNA对照组,并设不给予任何转染的空白对照组。免疫印迹(Western Blotting)法检测磷酸化ERK1/2(p-ERK)1/2和Notch2蛋白的表达水平。比色法(MTT)检测癌细胞增殖抑制率。结果Notch2siRNA能降低蛋白Notch2的表达水平,并抑制癌细胞增殖[(38.26±1.82)%],而p-ERK的表达水平则较对照组增加。PD98059能降低p-ERK的表达水平,并抑制癌细胞的增殖[(30.05±3.16)%],Notch2水平则无明显变化,联合应用Notch2siRNA和PD98059能明显降低p-ERK和Notch2蛋白的表达水平,与Notch2siRNA或PD98059单独应用比较,显著抑制癌细胞增殖率,差异有统计学意义[(72.55±5.30)%,P0.01]。结论特异性抑制Notch2信号通路,且抑制MEK/ERK通路可进一步增强抑制Notch2通路的抗肿瘤增殖效果,提示MEK/ERK和Notch2 2条信号通路在胃癌SGC-7901细胞中存在交叉作用。 相似文献