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1.
Reading PC Bozza S Gilbertson B Tate M Moretti S Job ER Crouch EC Brooks AG Brown LE Bottazzi B Romani L Mantovani A 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(5):3391-3398
Proteins of the innate immune system can act as natural inhibitors of influenza virus, limiting growth and spread of the virus in the early stages of infection before the induction of adaptive immune responses. In this study, we identify the long pentraxin PTX3 as a potent innate inhibitor of influenza viruses both in vitro and in vivo. Human and murine PTX3 bound to influenza virus and mediated a range of antiviral activities, including inhibition of hemagglutination, neutralization of virus infectivity and inhibition of viral neuraminidase. Antiviral activity was associated with binding of the viral hemagglutinin glycoprotein to sialylated ligands present on PTX3. Using a mouse model we found PTX3 to be rapidly induced following influenza infection and that PTX3-/- mice were more susceptible than wild-type mice to infection by PTX3-sensitive virus strains. Therapeutic treatment of mice with human PTX3 promoted survival and reduced viral load in the lungs following infection with PTX3-sensitive, but not PTX3-resistant, influenza viruses. Together, these studies describe a novel antiviral role for PTX3 in early host defense against influenza infections both in vitro and in vivo and describe the therapeutic potential of PTX3 in ameliorating disease during influenza infection. 相似文献
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Characterization of the long pentraxin PTX3 as a TNFalpha-induced secreted protein of adipose cells 总被引:3,自引:0,他引:3
Abderrahim-Ferkoune A Bezy O Chiellini C Maffei M Grimaldi P Bonino F Moustaid-Moussa N Pasqualini F Mantovani A Ailhaud G Amri EZ 《Journal of lipid research》2003,44(5):994-1000
Exposure of preadipocytes to long-chain fatty acids induces the expression of several markers of adipocyte differentiation. In an attempt to identify novel genes and proteins that are regulated by fatty acids in preadipocytes, we performed a substractive hybridization screening and identified PTX3, a protein of the pentraxin family. PTX3 mRNA expression is transient during adipocyte differentiation of clonal cell lines and is absent in fully differentiated cells. Stable overexpression of PTX3 in preadipocytes has no effect on adipocyte differentiation. In line with this, PTX3 mRNA is expressed in the stromal-vascular fraction of adipose tissue, but not in the adipocyte fraction; however, in 3T3-F442A adipocytes, the PTX3 gene can be reinduced by tumor necrosis factor alpha (TNFalpha) in a dose-dependent manner. This effect is accompanied by PTX3 protein secretion from both 3T3-F442A adipocytes and explants of mouse adipose tissue. PTX3 mRNA levels are found to be higher in adipose tissue of genetically obese mice versus control mice, consistent with their increased TNFalpha levels. In conclusion, PTX3 appears as a TNFalpha-induced protein that provides a new link between chronic low-level inflammatory state and obesity. 相似文献
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Gout E Moriscot C Doni A Dumestre-Pérard C Lacroix M Pérard J Schoehn G Mantovani A Arlaud GJ Thielens NM 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(10):5815-5822
Ficolins and pentraxins are soluble oligomeric pattern-recognition molecules that sense danger signals from pathogens and altered self-cells and might act synergistically in innate immune defense and maintenance of immune tolerance. The interaction of M-ficolin with the long pentraxin pentraxin 3 (PTX3) has been characterized using surface plasmon resonance spectroscopy and electron microscopy. M-ficolin was shown to bind PTX3 with high affinity in the presence of calcium ions. The interaction was abolished in the presence of EDTA and inhibited by N-acetyl-D-glucosamine, indicating involvement of the fibrinogen-like domain of M-ficolin. Removal of sialic acid from the single N-linked carbohydrate of the C-terminal domain of PTX3 abolished the interaction. Likewise, an M-ficolin mutant with impaired sialic acid-binding ability did not interact with PTX3. Interaction was also impaired when using the isolated recognition domain of M-ficolin or the monomeric C-terminal domain of PTX3, indicating requirement for oligomerization of both proteins. Electron microscopy analysis of the M-ficolin-PTX3 complexes revealed that the M-ficolin tetramer bound up to four PTX3 molecules. From a functional point of view, immobilized PTX3 was able to trigger M-ficolin-dependent activation of the lectin complement pathway. These data indicate that interaction of M-ficolin with PTX3 arises from its ability to bind sialylated ligands and thus differs from the binding to the short pentraxin C-reactive protein and from the binding of L-ficolin to PTX3. The M-ficolin-PTX3 interaction described in this study represents a novel case of cross-talk between soluble pattern-recognition molecules, lending further credit to the integrated view of humoral innate immunity that emerged recently. 相似文献
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Rivieccio V Esposito A Bellofiore P Palladino P Sassano M Colombo M Verdoliva A 《Protein expression and purification》2007,51(1):49-58
PTX3 is a secreted multimeric glycoprotein which plays a key role in innate immunity by activating the classical complement pathway through specific recognition of the C1q subunit. A method is described for the high level expression of the recombinant human PTX3 in Chinese hamster ovary cells (CHO), adapted to a suspension growth in spinner flasks containing a serum-free chemically defined medium and producing about 50 mg of PTX3/L of culture. A purification procedure to produce a homogeneous protein preparation from the supernatant, by means of anion exchange, hydroxyapatite and size exclusion chromatography, is also reported. This three-step protocol allows us to obtain PTX3 with a recovery yield close to 70%, a purity degree exceeding 95%, and a final host cell protein (HCP) content lower than 150 ppm. The recombinant purified PTX3 retains its biological activity, as demonstrated by C1q binding ELISA assay, and displays a complex quaternary structure characterized by a high secondary structure content quite different from human short pentraxin C-reactive protein (CRP) and serum amyloid P component (SAP), as determined by circular dichroism, fluorescence analysis, and native and SDS-PAGE experiments. 相似文献
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Lech M Römmele C Kulkarni OP Susanti HE Migliorini A Garlanda C Mantovani A Anders HJ 《PloS one》2011,6(5):e20118
The long pentraxin PTX3 has multiple roles in innate immunity. For example, PTX3 regulates C1q binding to pathogens and dead cells and regulates their uptake by phagocytes. It also inhibits P-selectin-mediated recruitment of leukocytes. Both of these mechanisms are known to be involved in autoimmunity and autoimmune tissue injury, e.g. in systemic lupus erythematosus, but a contribution of PTX3 is hypothetical. To evaluate a potential immunoregulatory role of PTX3 in autoimmunity we crossed Ptx3-deficient mice with Fas-deficient (lpr) C57BL/6 (B6) mice with mild lupus-like autoimmunity. PTX3 was found to be increasingly expressed in kidneys and lungs of B6lpr along disease progression. Lack of PTX3 impaired the phagocytic uptake of apoptotic T cells into peritoneal macrophages and selectively expanded CD4/CD8 double negative T cells while other immune cell subsets and lupus autoantibody production remained unaffected. Lack of PTX3 also aggravated autoimmune lung disease, i.e. peribronchial and perivascular CD3+ T cell and macrophage infiltrates of B6lpr mice. In contrast, histomorphological and functional parameters of lupus nephritis remained unaffected by the Ptx3 genotype. Together, PTX3 specifically suppresses autoimmune lung disease that is associated with systemic lupus erythematosus. Vice versa, loss-of-function mutations in the Ptx3 gene might represent a genetic risk factor for pulmonary (but not renal) manifestations of systemic lupus or other autoimmune diseases. 相似文献
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Structure and function of the long pentraxin PTX3 glycosidic moiety: fine-tuning of the interaction with C1q and complement activation 总被引:4,自引:0,他引:4
Inforzato A Peri G Doni A Garlanda C Mantovani A Bastone A Carpentieri A Amoresano A Pucci P Roos A Daha MR Vincenti S Gallo G Carminati P De Santis R Salvatori G 《Biochemistry》2006,45(38):11540-11551
The prototypic long pentraxin PTX3 is a unique fluid-phase pattern recognition receptor that plays a nonredundant role in innate immunity and female fertility. The PTX3 C-terminal domain is required for C1q recognition and complement activation and contains a single N-glycosylation site on Asn 220. In the present study, we characterized the structure of the human PTX3 glycosidic moiety and investigated its relevance in C1q interaction and activation of the complement classical pathway. By specific endo and exoglycosidases digestion and direct mass spectrometric analysis, we found that both recombinant and naturally occurring PTX3 were N-linked to fucosylated and sialylated complex-type sugars. Interestingly, glycans showed heterogeneity mainly in the relative amount of bi, tri, and tetrantennary structures depending on the cell type and inflammatory stimulus. Enzymatic removal of sialic acid or the entire glycosidic moiety equally enhanced PTX3 binding to C1q compared to that in the native protein, thus indicating that glycosylation substantially contributes to modulate PTX3/C1q interaction and that sialic acid is the main determinant of this contribution. BIAcore kinetic measurements returned decreasing K(off) values as sugars were removed, pointing to a stabilization of the PTX3/C1q complex. No major rearrangement of PTX3 quaternary structure was observed after desialylation or deglycosylation as established by size exclusion chromatography. Consistent with C1q binding, PTX3 desialylation enhanced the activation of the classical complement pathway, as assessed by C4 and C3 deposition. In conclusion, our results provided evidence of an involvement of the PTX3 sugar moiety in C1q recognition and complement activation. 相似文献
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Rupprecht TA Angele B Klein M Heesemann J Pfister HW Botto M Koedel U 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(3):1861-1869
Previous studies suggest that the complement system can contribute to limiting pneumococcal outgrowth within the CNS. In this study, we evaluated the role of the complement system in the activation of the innate immune response and the development of the prognosis-relevant intracranial complications in a murine model of pneumococcal meningitis. Thereby, we used mice deficient in C1q, lacking only the classical pathway, and C3, lacking all three complement activation pathways. At 24 h after intracisternal infection, bacterial titers in the CNS were almost 12- and 20-fold higher in C1q- and C3-deficient-mice, respectively, than in wild-type mice. Mean CSF leukocyte counts were reduced by 47 and 73% in C1q- and C3-deficient-mice, respectively. Intrathecal reconstitution with wild-type serum in C3-deficient mice restored both the ability of mice to combat pneumococcal infection of the CSF and the ability of leukocytes to egress into the CSF. The altered recruitment of leukocytes into the CSF of C3-deficient mice was paralleled by a strong reduction of the brain expression of cytokines and chemokines. The dampened immune response in C3-deficient mice was accompanied by a reduction of meningitis-induced intracranial complications, but, surprisingly, also with a worsening of short-term outcome. The latter seems to be due to more severe bacteremia (12- and 120-fold higher in C1q- and C3-deficient-mice, respectively) and, consecutively, more severe systemic complications. Thus, our study demonstrated for the first time that the complement system plays an integral role in mounting the intense host immune response to Streptococcus pneumoniae infection of the CNS. 相似文献
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Fine-tuning of the innate immune response by microRNAs 总被引:1,自引:0,他引:1
MicroRNAs (miRNAs) are emerging as potent regulators of many biological processes, including cellular differentiation and disease. Recently, miRNA has been directly involved in innate immunity and transduction signalling by Toll-like receptors and the ensuing cytokine response. In this review, we present an overview of what is currently known of the involvement of miRNA and RNA interference components in the fine-tuning of innate immune responses. 相似文献
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Kaiser A Donnadieu E Abastado JP Trautmann A Nardin A 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(4):2349-2356
For immune responses to take place, naive T cells have to encounter, adhere to, and be stimulated by dendritic cells (DCs). In murine lymph nodes, T cells move randomly and scan the surface of multiple DCs. The factors controlling this motility as well as its consequences remain unclear. We have monitored by video-imaging the earliest steps of the interaction between human DCs and autologous naive CD4+ T cells in the absence of exogenous Ags. Mature, but not immature, DCs were able to elicit small calcium responses in naive T cells along with cell polarization and random motility, resulting in an efficient scanning of DC surfaces by T cells. We identified CCL19 as a key factor enabling all these early T cell responses, including the occurrence of calcium transients. Because this chemokine did not influence the strength of naive T cell adhesion to DCs, enhanced LFA-1 affinity for ICAM-1 was not the main mechanism by which CCL19 increased Ag-independent calcium transients. However, concomitantly to T cell motility, CCL19 augmented the frequency of T cell responses to rare anti-CD3/CD28-coated beads, used as surrogate APCs. We thus propose a new role for CCL19 in humans: by conditioning T cells into a motile DC-scanning state, this chemokine promotes Ag-independent responses and increases the probability of cognate MHC-peptide encounter. 相似文献
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Toxoplasma gondii is a unique intracellular parasite. It can infect a variety of cells in virtually all warm-blooded animals. It has a worldwide distribution and, overall, around one-third of people are seropositive for the parasite, with essentially the entire human population being at risk of infection. For most people, T. gondii causes asymptomatic infection but the parasite can cause serious disease in the immunocompromised and, if contracted for the first time during pregnancy, can cause spontaneous abortion or congenital defects, which have a substantial emotional, social and economic impact. Toxoplasma gondii provokes one of the most potent innate, pro-inflammatory responses of all infectious disease agents. It is also a supreme manipulator of the immune response so that innate immunity to T. gondii is a delicate balance between the parasite and its host involving a coordinated series of cellular interactions involving enterocytes, neutrophils, dendritic cells, macrophages and natural killer cells. Underpinning these interactions is the regulation of complex molecular reactions involving Toll-like receptors, activation of signalling pathways, cytokine production and activation of anti-microbial effector mechanisms including generation of reactive nitrogen and oxygen intermediates. 相似文献
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Yokouchi H Fukuoka Y Mukoyama D Calugay R Takeyama H Matsunaga T 《Environmental microbiology》2006,8(7):1155-1163
Limitations in obtaining sufficient specimens and difficulties in extracting high quality DNA from environmental samples have impeded understanding of the structure of microbial communities. In this study, multiple displacement amplification (MDA) using phi29 polymerase was applied to overcome these hindrances. Optimization of the reaction conditions for amplification of the bacterial genome and evaluation of the MDA product were performed using cyanobacterium Synechocystis sp. strain PCC6803. An 8-h MDA reaction yielded a sufficient quantity of DNA from an initial amount of 0.4 ng, which is equivalent to approximately 10(5) cells. Uniform amplification of genes randomly selected from the cyanobacterial genome was confirmed by real-time polymerase chain reaction. The metagenome from bacteria associated with scleractinian corals was used for whole-genome amplification using phi29 polymerase to analyse the microbial diversity. Unidentified bacteria with less than 93% identity to the closest 16S rDNA sequences deposited in DNA Data Bank of Japan were predominantly detected from the coral-associated bacterial community before and after the MDA procedures. Sequencing analysis indicated that alpha-Proteobacteria was the dominant group in Pocillopora damicornis. This study demonstrates that MDA techniques are efficient for genome wide investigation to understand the actual microbial diversity in limited bacterial samples. 相似文献
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Two cytokine-inducible gene products, important in inflammation and infection, also play essential roles in female fertility. One of these is the product of tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6), alternatively termed TNFAIP6 (for TNF-alpha-induced protein 6), originally cloned from diploid human fibroblasts stimulated with TNF. The second is pentraxin 3 (PTX3), also termed TSG-14, originally isolated from TNF-stimulated human fibroblasts and from interleukin-1 (IL-1)-stimulated vascular endothelial cells. TSG-6, which specifically binds to hyaluronan (HA) and to inter-alpha-inhibitor (I alpha I), shows potent anti-inflammatory activity in acute and chronic inflammation, notably in several models of autoimmune arthritis. PTX3 was shown to play an important role in resistance to fungal infection with Aspergillus fumigatus. Both TSG-6 and PTX3 are synthesized in the ovary prior to ovulation, where they become components of an expanding viscoelastic matrix that surrounds the oocyte before its release from the follicle at the ovarian surface. Female mice with a targeted disruption of either the TSG-6 or PTX3 gene show severe defects in fertility. 相似文献
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Lemna gibba G3 in M-EDTA or M-EDTA-sucrose medium initiatesflowers in response to a single long day, but requires a minimumof nearly or exactly 2 long days in an M or M-sucrose mediumfor flower induction. (Received December 18, 1971; ) 相似文献
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Pneumococcal pneumonia is a leading cause of death and a major source of human morbidity. The initial immune response plays a central role in determining the course and outcome of pneumococcal disease. We combine bacterial titer measurements from mice infected with Streptococcus pneumoniae with mathematical modeling to investigate the coordination of immune responses and the effects of initial inoculum on outcome. To evaluate the contributions of individual components, we systematically build a mathematical model from three subsystems that describe the succession of defensive cells in the lung: resident alveolar macrophages, neutrophils and monocyte-derived macrophages. The alveolar macrophage response, which can be modeled by a single differential equation, can by itself rapidly clear small initial numbers of pneumococci. Extending the model to include the neutrophil response required additional equations for recruitment cytokines and host cell status and damage. With these dynamics, two outcomes can be predicted: bacterial clearance or sustained bacterial growth. Finally, a model including monocyte-derived macrophage recruitment by neutrophils suggests that sustained bacterial growth is possible even in their presence. Our model quantifies the contributions of cytotoxicity and immune-mediated damage in pneumococcal pathogenesis. 相似文献