共查询到20条相似文献,搜索用时 31 毫秒
1.
Scheel B Aulwurm S Probst J Stitz L Hoerr I Rammensee HG Weller M Pascolo S 《European journal of immunology》2006,36(10):2807-2816
Stabilized synthetic RNA oligonucleotides (ORN) and protected messenger RNA (mRNA) were recently discovered to possess an immunostimulatory capacity through their recognition by TLR 7 and 8. We wanted to find out whether this danger signal is capable of triggering anti-tumor immunity when injected locally into an established tumor. Using the mouse glioma tumor cell line SMA-560 in syngenic VM/Dk mice, we were able to show that intra-tumor injections of protamine-stabilized mRNA do indeed induce tumor regression and long-term anti-tumor immunity. Residual RNA-injected tumors show CD8 infiltration. Distant injections of protamine-protected mRNA and intra-tumor injection of naked mRNA also result in anti-tumor immunity. Although they are strong danger signals, RNA are labile molecules with a short half-life: they do not trigger side effects such as long-term, uncontrolled immunostimulation evidenced by splenomegaly in CpG DNA-treated mice. In conclusion, RNA molecules are potent and safe danger signals that are relevant for active immunotherapy strategies aimed at the eradication of solid tumors. 相似文献
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Scheel B Braedel S Probst J Carralot JP Wagner H Schild H Jung G Rammensee HG Pascolo S 《European journal of immunology》2004,34(2):537-547
Since direct injection of naked mRNA induces an immune response, we tested the capacity of RNA to signal danger. We show here that mRNA molecules that are protected from immediate degradation either through interaction with cationic proteins (trans protection) or through chemical modification of the phosphodiester backbone (phosphorothioate RNA; cis protection) act as sequence-independent danger signals on mouse DC. As opposed to CpG DNA, the cis-stabilized RNA is degraded in a few minutes, does not activate B cells and, in contrast to double-stranded RNA, requires MyD88 for activation of the DC. We postulate that phosphorothioate RNA, which mimics trans-stabilized RNA, is a new PAMP. 相似文献
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Ellen B Cook James L Stahl Stéphane Esnault Neal P Barney Frank M Graziano 《Annals of allergy, asthma & immunology》2005,94(4):486-497
BACKGROUND: Staphylococcus aureus colonization is common in atopic keratoconjunctivitis, potentially activating epithelial cells via toll-like receptor 2 (TLR-2) and the receptor for platelet-activating factor (PAFR). OBJECTIVES: To examine human conjunctival epithelial cells for the expression of TLR-2 in vitro and in vivo and to evaluate the role of TLR-2 in S aureus-mediated activation of these cells. METHODS: Conjunctival epithelial cells isolated from cadaveric tissues were stimulated with interferon gamma (IFN-gamma) or a commercial S aureus cell wall extract (Staphylococcus aureus-CWE) (with or without anti-TLR-2 blocking antibody or PAFR antagonist) and were analyzed for tumor necrosis factor alpha (TNF-alpha) and interleukin 8 (IL-8) release; surface expression of TLR-2, intercellular adhesion molecule-1, HLA, and CD14; and TLR-2 messenger RNA expression. Ocular surface cells collected via impression cytology were examined for TLR-2 expression via flow cytometry. RESULTS: Expression of TLR-2 was up-regulated on conjunctival epithelial cells by IFN-gamma and Staphylococcus aureus-CWE. Expression of TLR-2 messenger RNA was increased by IFN-gamma. Staphylococcus aureus-CWE up-regulated intercellular adhesion molecule 1, HLA, and CD14 expression and increased TNF-alpha and IL-8 release in a dose-dependent manner. Anti-TLR-2 significantly inhibited TNF-alpha release, whereas PAFR antagonist significantly inhibited IL-8 release. Toll-like receptor 2 was expressed on conjunctival epithelial cells from 4 of 5 patients with atopic keratoconjunctivitis, 3 of 5 with seasonal allergies, and 0 of 3 without allergies. CONCLUSIONS: Conjunctival epithelial cells express TLR-2 and may play an active role in the chronic ocular inflammatory response to S aureus through pathways that involve TLR-2 and PAFR. 相似文献
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TLR-9 Activation of Marginal Zone B Cells in Lupus Mice Regulates Immunity Through Increased IL-10 Production 总被引:15,自引:0,他引:15
Bacterial DNA triggers B-cell proliferation and induces immunoglobulin secretion. Chromatin–IgG complexes activate autoreactive B cells by co-engaging B-cell receptor (BCR) and TLR-9, thus suggesting a role for innate signaling in systemic autoimmunity. Spleen cells from lupus prone Palmerston North (PN) mice produce several fold less IL-12p40 than controls in response to CpG–oligodeoxynucleotides (ODNs). Here we show that B cells are primarily responsible for this abnormality. The removal of B cells from PN cultures markedly increased IL-12p40. Moreover, the addition of purified B cells back to PN splenocyte cultures resulted in a B-cell number dependent/ IL-10-mediated suppression of IL-12p40. The B cells were the major source of IL-10. In response to CpG, B cells from several lupus strains produced twice as a much IL-10 as controls, but failed to produce IL-10 when stimulated through BCR or CD40. PN and control mice expressed IL-10R similarly, and the difference in IL-10 secretion remained when anti-IL-10R blocking antibodies were used. IFN- and IL-4 regulated CpG-induced IL-10 secretion in opposite directions. The abnormal IL-10 response in lupus mice was derived from B cells with the marginal zone phenotype, and could be downregulated with inhibitory ODNs. We hypothesize that TLR-9 activated lupus B cells can modulate T-cell mediated inflammatory responses through IL-10 production. Therefore, B cells may contribute to the lupus pathogenesis in many different ways: as antigen-presenting cells for self antigens, as effector cells for autoantibody production, and as IL-10 secreting regulatory cells. 相似文献
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Cells respond to viral infection through induction of discrete, innate immune response pathways that lead to induction of interferons (IFNs) and other proinflammatory cytokines, as well as the direct induction of some IFN-responsive genes that mediate specific antiviral or immunomodulatory responses. To assess the classes of genes induced directly upon treatment of cells with double-stranded RNA (dsRNA), a mimic of viral infection, we made use of a mutant human cell line defective in responsiveness to dsRNA and IFN. P2.1 mutant cells were generated from a Jak1-minus, HT1080 fibrosarcoma-derived cell line (U4C) after extensive mutagenesis with the intercalating agent ICR191. We now demonstrate that P2.1 cells are defective in basal and induced expression of toll-like receptor-3 (TLR-3), which may contribute to their dsRNA-unresponsive phenotype. After transfection with a wild-type TLR-3 gene, P2.1 cells were largely responsive to a dsRNA challenge, as assessed by activation of NF-kappaB and IFN regulatory factors (IRFs) and induction of IFN-beta and other genes. Untransfected and TLR-3-transfected P2.1 cells were assessed for global dsRNA responsiveness in oligonucleotide gene array studies alongside parental U4C and HT1080 cells. Several distinct patterns of gene induction in response to dsRNA challenge were identified, including genes expressed in a TLR-3-dependent manner, genes that required an intact IFN feedback for expression, and dsRNA-responsive genes that appeared not to require TLR-3 for induction. These data support the hypothesis that TLR-3 is an important determinant of cellular responses to external dsRNA and demonstrate distinctions in the repertoires of dsRNA-regulated genes induced when the IFN-feedback loop is present or absent in cells. 相似文献
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Leishmania lipophosphoglycan (LPG) activates NK cells through toll-like receptor-2 总被引:10,自引:0,他引:10
Becker I Salaiza N Aguirre M Delgado J Carrillo-Carrasco N Kobeh LG Ruiz A Cervantes R Torres AP Cabrera N González A Maldonado C Isibasi A 《Molecular and biochemical parasitology》2003,130(2):65-74
Toll-like receptors (TLRs) mediate the cellular response to conserved molecular patterns shared by microorganisms. We report that TLR-2 on human NK cells is upregulated and stimulated by Leishmania major lipophosphoglycan (LPG), a phosphoglycan belonging to a family of unique Leishmania glycoconjugates. We found that purified L. major LPG upregulates both mRNA and the membrane expression of TLR-2 in NK cells. Additionally, IFN-gamma and TNF-alpha production and nuclear translocation of NF-kappaB was enhanced. The activation effect was more intense with LPG purified from infectious metacyclic parasites than from noninfectious procyclic Leishmania. Since the difference between the molecules derived from these two stages of the parasite growth cycle lies exclusively in the number of phosphosaccharide repeat domains and in the composition of glycan side chains that branch off these domains, we propose that TLR-2 possibly distinguishes between phosphorylated glycan repeats on LPG molecules. The effect of LPG on cytokine production and on membrane expression of TLR-2 could be blocked with F(ab')2 fragments of the mAb against LPG (WIC 79.3). Confocal microscopy demonstrated the co-localization of LPG and TLR-2 on the NK cell membrane. Binding of LPG to TLR-2 in NK cells was demonstrated by immunoprecipitations done with anti-TLR-2 and anti-LPG mAb followed by immunoblotting with anti-LPG and anti-TLR-2, respectively. Both antibodies recognized the immune complexes. These results suggest that NK cells are capable of recognition of, and activation by, Leishmania LPG through TLR-2, enabling them to participate autonomously in the innate immune system and thereby increasing the effective destruction of the parasite. 相似文献
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Zeiser R Penack O Holler E Idzko M 《Journal of molecular medicine (Berlin, Germany)》2011,89(9):833-845
Extensive cell death with consecutive release of danger signals can cause immune-mediated tissue destruction. The abundance
of cell death is likely to determine the relevance of the danger signals as physiological mechanisms that counteract immune
activation may be overruled. Such constellation is conceivable in chemo-/radiotherapy-induced tissue damage, reperfusion injury,
trauma, and severe infection. Studies on graft-versus-host disease (GvHD) development have to consider the effects of chemo-/radiotherapy-related
tissue damage leading to the release of exogenous and endogenous danger signals. Our previous work has demonstrated a role
for adenosine-5′-triphosphate (ATP) as an endogenous danger signal in GvHD. Besides ATP, uric acid or soluble extracellular
matrix components are functional danger signals that activate the NLRP3 inflammasome when released from dying cells or from
extracellular matrix. In contrast to sterile inflammation, GvHD is more complex since bacterial components that leak through
damaged intestinal barriers and the skin can activate pattern recognition receptors and directly contribute to GvHD pathogenesis.
These exogenous danger signals transmit immune activation via toll-like receptors and NOD-like receptors of the innate immune
system. This review covers both the impact of endogenous and exogenous danger signals activating innate immunity in GvHD. 相似文献
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BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas-mediated cell death 总被引:2,自引:0,他引:2
Acosta-Rodríguez EV Craxton A Hendricks DW Merino MC Montes CL Clark EA Gruppi A 《European journal of immunology》2007,37(4):990-1000
Microorganisms with pathogen-associated molecular patterns (PAMP) activate B cells directly by binding to TLR and also indirectly by inducing APC to release cytokines such as BAFF that promote B cell survival. We found that murine B cells activated concomitantly with LPS (TLR-4 ligand) and BAFF are protected from spontaneous apoptosis, but are more susceptible to Fas/CD95-mediated cell death. This increased susceptibility to Fas-induced apoptosis is associated with a dramatic coordinated up-regulation of Fas/CD95 and IRF-4 expression through a mechanism mediated, at least in part, by inhibition of the MEK/ERK pathway. Up-regulation of Fas/CD95 by BAFF is restricted to B cells activated through TLR-4, but not through TLR-9, BCR or CD40. TLR ligands differ in the BAFF family receptors (R) they induce on B cells: BAFF-R is increased by the TLR4 ligand, LPS, but not by the TLR9 ligand, CpG-containing oligodeoxynucleotides, which, in contrast, strongly up-regulates transmembrane activator and CAML interactor (TACI). This suggests the up-regulation of Fas by BAFF is mediated by BAFF-R and not by TACI. Consistently, APRIL, which binds to TACI and B cell maturation antigen but not BAFF-R, did not enhance Fas expression on LPS-activated B cells. Increased susceptibility to Fas-mediated killing of B cells activated with LPS and BAFF may be a fail-safe mechanism to avoid overexpansion of nonspecific or autoreactive B cells. 相似文献
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Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3 总被引:9,自引:0,他引:9
Kulka M Alexopoulou L Flavell RA Metcalfe DD 《The Journal of allergy and clinical immunology》2004,114(1):174-182
BACKGROUND: Although mast cells (MCs) have been clearly implicated in innate immune responses involving bacteria, their ability to respond to viral infection is less clear. OBJECTIVE: Given that MCs increase at sites of inflammation and are located at surfaces where exposure to invading viruses may occur, we explored the ability of MCs to produce cytokines including type I IFNs after exposure to viruses and to polyinosine-polycytidylic acid (polyI:C), a synthetic mimic of viral double-stranded RNA, and characterized the receptors involved, if any. METHODS: Human peripheral blood-derived cultured MCs and 2 MC lines, Laboratory of Allergic Disease MC line and human MC line 1, were stimulated with viruses and polyI:C, and cytokine production, degranulation, and signaling pathway activation were examined. Because polyI:C is a ligand for Toll-like receptor (TLR)-3, human MCs were also analyzed for TLR expression. RESULTS: Viruses and polyI:C induced IFN-alpha and IFN-beta production. PolyI:C did not induce TNF, IL-1beta, IL-5, or GM-CSF production, in contrast with other TLR ligands (LPS, peptidoglycan, CpG-A, or flagellin). IFN-alpha production involved nuclear factor-kappaB, p38, and C-Jun NH2-terminal kinase and mitogen-activated protein kinase. RT-PCR and Western blot analysis confirmed expression of TLR-3 by all MCs. Human cultured MCs also expressed TLR-1, TLR-2, TLR-4, TLR-5, TLR-6, TLR-7 and TLR-9. Antibodies to TLR-3 significantly decreased IFN-alpha production. Bone marrow-derived MCs from TLR-3 knockout mice showed an ablated response to polyI:C. CONCLUSIONS: Murine and human MCs produce type I IFNs after exposure to double-stranded RNA and/or virus, the former via specific interactions with TLR-3. These data suggest that MCs contribute to innate immune responses to viral infection via the production of type I IFNs. 相似文献
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Activation of toll-like receptor 9 by DNA from different bacterial species 总被引:4,自引:0,他引:4
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Toll-like receptor 9 (TLR-9) recognizes unmethylated CpG dinucleotides which are abundant in prokaryotic DNA and yet are rare in eukaryotic DNA. Little is known about the significance of TLR-9 in terms of recognition of different bacterial DNA species. In this study HEK293 cells stably transfected with human TLR-9 were used to analyze the immunostimulatory properties of 15 bacterial DNA preparations. In addition, bacterial genome data were analyzed for the frequency of unmethylated cytosine-guanosine ([CG]) dinucleotides. We observed that DNA samples of different bacteria showed considerable differences in their potential to stimulate TLR-9. This correlated with the frequency of [CG] dinucleotides. Based upon data from our experiments the estimate of immunostimulatory bacterial DNA concentrations translated to as high as 10(9) bacteria/ml. Application of the transfection reagent DOTAP resulted in a more efficient delivery of DNA into the cell, and this went along with increased TLR-9 activation. The data indicate that bacterial DNA preparations from different species differ in their capacity to activate TLR-9, which is dependent on the individual [CG] content. Moreover, increased intracellular delivery results in a marked enhancement of immunostimulation. 相似文献
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《Expert Review of Clinical Immunology》2013,9(1):61-77
Inflammasomes are recently discovered molecular complexes that can sense danger signals and specifically activate caspase-1 and -5 and proinflammatory cytokines (IL-1β and IL-18). Upon signaling, the inflammasome complex forms around a NOD-like receptor family member that serves both as a danger sensor and as a recruiting platform. The number of known triggers that stimulate inflammasomes is rapidly rising, ranging from genetic mutations to microbial products, gout crystals, ultraviolet light and adjuvant chemicals. As a result of this surprising diversity, the inflammasome may have a significant impact on most medical fields. A good understanding of the molecular mechanisms underlying its activation/regulation is essential today, as several therapeutic and diagnostic tools have already reached the bedside, and more are sure to come. 相似文献
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Biragyn A Coscia M Nagashima K Sanford M Young HA Olkhanud P 《Journal of leukocyte biology》2008,83(4):998-1008
Mammalian antimicrobial peptides, including beta-defensins, represent an ancient arm of innate immunity designed to directly neutralize invading microbes. Previously, we demonstrated that murine beta-defensin 2 (mDF2beta) also acted as an endogenous ligand for TLR-4-activating maturation of dendritic cells (DCs). Herein, we report that this TLR-4 -dependent activation leads to induction of an atypical cell death that is unexpectedly exaggerated by the inhibition of caspases. Experiments using APCs with nonfunctional TNF-alpha or its receptors suggest that this is a NF-kappaB- and TNF-alpha-dependent process that does not require TNFR1. We demonstrate that mDF2beta triggers a TNFR2-mediated signaling cascade of "self-destruction" through up-regulation of membrane-bound TNF-alpha and TNFR2. This appears not to be an isolated phenomenon, as human synthetic beta-defenisn 3 was also able to activate and kill DCs. We propose that beta-defenins may play an important immunoregulatory role as controllers of the natural process of elimination of activated APCs. 相似文献
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Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses 总被引:12,自引:0,他引:12
Yang K Puel A Zhang S Eidenschenk C Ku CL Casrouge A Picard C von Bernuth H Senechal B Plancoulaine S Al-Hajjar S Al-Ghonaium A Maródi L Davidson D Speert D Roifman C Garty BZ Ozinsky A Barrat FJ Coffman RL Miller RL Li X Lebon P Rodriguez-Gallego C Chapel H Geissmann F Jouanguy E Casanova JL 《Immunity》2005,23(5):465-478
Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans. 相似文献
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Stevenson R Fatehullah A Jagan I Deevi RK Bingham V Irvine AE Armstrong M Morrison PJ Dimmick I Stewart R Campbell FC 《Clinical and experimental immunology》2011,165(2):202-210
Dendritic cells (DCs) are the most potent antigen-presenting cells and play a crucial role by modulating the T cell immune response against infective agents, tumour antigens and alloantigens. The current study shows that differentiating bone marrow (BM)-derived DCs but not fully differentiated DCs are targets of erythropoietin (EPO). Indeed, DCs emerging from rat bone marrow, but not splenic DCs, express the EPO receptor (Epo-R) and respond to EPO stimulation displaying a more activated phenotype with increased CD86, CD40 and interleukin (IL)-12 expression levels and a higher allostimulatory capacity on T cells than untreated DCs. Moreover, results here presented show that EPO up-regulates Toll-like receptor (TLR)-4 in differentiating DCs rendering these cells more sensitive to stimulation by the TLR-4 ligand lipopolysaccharide (LPS). Indeed, DCs treated with EPO and then stimulated by LPS were strongly allostimulatory and expressed CCR7, CD86, CD40, IL-12 and IL-23 at higher levels than those observed in DCs stimulated with LPS alone. It is tempting to speculate that EPO could act as an additional danger signal in concert with TLR-4 engagement. Thus, EPO, beyond its erythropoietic and cytoprotective effects, turns out to be an immune modulator. 相似文献