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At least 109 records · Page 6Linked to original sources
PubMed2006

Stimulation of innate immune responses by CpG oligodeoxynucleotide in newborn lambs can reduce bovine herpesvirus-1 shedding.

Stimulation of the innate immune system is potentially very important in neonates who have an immature adaptive immune system and vaccination cannot be used to reduce the risk of infection. CpG oligodeoxynucleotide (ODN) can stimulate innate immune responses in newborn chickens and mice, but similar studies are lacking in other mammalian species. We have shown previously that CpG ODN can both stimulate an acute-phase immune response and induce the antiviral effector molecule, 2'5'-A synthetase, in adult sheep. Therefore, the immunostimulatory activity of A class and B class CpG ODN was evaluated in newborn lambs, and the capacity of CpG ODN-induced responses to reduce viral shedding was evaluated following aerosol challenge with the respiratory pathogen, bovine herpesvirus-1 (BHV-1). In vitro CpG ODN stimulation of peripheral blood mononuclear cells (PBMC) isolated from newborn lambs (3-5 days old) and adult sheep induced equivalent CpG-specific proliferative responses and interferon-alpha (IFN-alpha) secretion. CpG ODN-induced IFN-alpha secretion by neonatal PBMCs was, however, significantly (p < 0.01) enhanced 6 days after subcutaneous (s.c.) injection of 100 microg/kg CpG ODN 2007. Newborn lambs injected s.c. with B class CpG ODN 2007 or the inverted GpC control ODN formulated in 30% Emulsigen (MVP Laboratories, Ralston, NE) displayed CpG ODN-specific increases in body temperature (p < 0.0001), serum 2'5'-A synthetase activity (p = 0.0015), and serum haptoglobin (p = 0.07). CpG ODN-treated lambs also displayed a transient reduction in viral shedding on day 2 postinfection (p < 0.05), which correlated (p < 0.03) with serum 2'5'-A synthetase levels on the day of viral challenge. These observations confirmed that CpG ODNs effectively activate innate immune responses in newborn lambs and CpG ODN-induced antiviral responses correlated with a reduction in viral shedding.

Adjuvants, Immunologic↗
PubMed2006

Macrophages are essential for antitumour effects against weakly immunogenic murine tumours induced by class B CpG-oligodeoxynucleotides.

We explored the mechanisms of class B CpG-oligodeoxynucleotide-induced antitumour effects against weakly immunogenic tumours. Treatment with CpG-oligodeoxynucleotide 1826 (CpG) induced similar antitumour effects in B16 melanoma-bearing immunocompetent C57BL/6 mice and T-cell-deficient severe combined immunodeficient (SCID) mice, and NXS2 neuroblastoma-bearing T-cell-depleted A/J mice. Both macrophages (Mphi) and natural killer (NK) cells from CpG-treated C57BL/6 mice could mediate cytotoxicity in vitro, suggesting that these cell types might control tumour growth in vivo. However, CpG treatment of SCID/beige mice or T-cell-depleted and NK-cell-depleted A/J mice still induced antitumour effects in vivo, arguing against a major role of NK cells in the antitumour effects of CpG in the absence of T cells. In contrast, CpG treatment of interferon-gamma knockout (IFN-gamma(-/-)) C57BL/6 mice resulted in no antitumour effects in vivo and no Mphi-mediated tumoristasis in vitro despite unaltered cytolytic function of NK cells in vitro. Moreover, Mphi inactivation by silica substantially reduced CpG-induced suppression of tumour growth in vivo, revealing an important role of Mphi in CpG-induced antitumour effects. The in vitro tumouritoxicity by CpG-stimulated Mphi (CpG-Mphi) correlated with tumour cell mitochondria dysfunction and involved nitric oxide (NO), tumour necrosis factor-alpha (TNF-alpha) and IFN-gamma, whereas interleukin-1alpha (IL-1alpha), IL-1beta, IFN-alpha, TNF-related apoptosis-inducing ligand and Fas ligand played insignificant roles in CpG-Mphi tumouritoxicity. Taken together, our results indicate that the growth control of weakly immunogenic tumours during CpG-immunotherapy is mediated predominantly by Mphi, rather than T cells or NK cells.

Animals↗
PubMed2006

Response of nitric oxide production to CpG oligodeoxynucleotides in turkey and chicken peripheral blood monocytes.

We evaluated the innate immune response to various synthetic CpG-containing oligodeoxynucleotides (CpG ODNs) by measuring nitric oxide production in the peripheral blood monocytes from turkey poults. The results indicate that the presence of the CpG dinucleotide in ODNs was a prerequisite for activation of turkey monocytes and induction of nitric oxide (NO) synthesis. CpG motifs and sequence structure of the ODNs were also found to influence stimulatory activity greatly. The most potent CpG ODN to induce NO synthesis in turkey monocytes was human-specific CpG ODN M362, followed by CpG ODN 2006 (human), CpG ODN#17 (chicken) and CpG ODN 1826 (mouse). The optimal CpG motif for NO induction was GTCGTT. Phosphorothioate modification of CpG ODNs also significantly increased stimulatory activity. Compared with chicken monocytes, turkey monocytes appeared to be less sensitive to CpG motif variation, whereas chicken monocytes were found to respond more strictly to human-specific CpG ODNs or ODNs that contain GTCGTT motifs.

Animals↗
PubMed2005

Anti-HBV effects of CpG oligodeoxynucleotide-activated peripheral blood mononuclear cells from patients with chronic hepatitis B.

Unmethylated CpG dinucleotides in bacterial DNA or synthetic oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG ODN) are known as a potent Th1-like immune enhancer in vertebrates. Chronic hepatitis B is the immunocompromising condition. We therefore investigated the effects of CpG ODN on cultured cells from chronic hepatitis B patients and healthy controls. The inhibitory effects of CpG ODN on hepatitis B virus (HBV) were also studied. The secretion of IFN-alpha by CpG ODN-activated peripheral blood mononuclear cells (PBMCs) from chronic hepatitis B patients and healthy controls was significantly increased when compared with PBMCs alone or GpC ODN-stimulated PBMCs. After activation with CpG ODN, the IFN-alpha secretion by chronically HBV-infected patient PBMCs is less than that by healthy control PBMCs. Treatment of HepG2 2.2.15 cells with culture supernatants of PBMCs activated by CpG ODN can significantly suppress the secretion of HBsAg, HBeAg and HBV DNA as compared with that of PBMCs without CpG ODN activation under the same conditions. No inhibitory effect on the replication of HBV was found for CpG ODN treatment alone. Our results indicated that CpG ODN could efficiently enhance the immune response of chronic hepatitis B patients. Moreover, the CpG ODN-activated PBMCs from chronic hepatitis B patients were able to significantly inhibit HBV replication in vitro, suggesting that CpG ODN may be a potential immunoregulator against HBV infection in the future.

Adult↗
PubMed1999

CpG-containing oligonucleotides are efficient adjuvants for induction of protective antiviral immune responses with T-cell peptide vaccines.

Synthetic nonmethylated oligonucleotides containing CpG dinucleotides (CpG-ODNs) have been shown to exhibit immunostimulatory activity. CpG-ODNs have the capacity to directly activate B cells, macrophages, and dendritic cells, and we show here that this is reflected by cell surface binding of oligonucleotides to these cell subsets. However, T cells are not directly activated by CpG-ODNs, which correlates with the failure to bind to the T-cell surface. Efficient competition for CpG-induced B-cell activation by non-CpG-containing oligonucleotides suggests that oligonucleotides might bind to an as yet undefined sequence-nonspecific receptor prior to cellular activation. Induction of protective T-cell responses against challenge infection with lymphocytic choriomeningitis virus (LCMV) or with recombinant vaccinia virus expressing the LCMV glycoprotein was achieved by immunizing mice with the immunodominant major histocompatibility complex class I-binding LCMV glycoprotein-derived peptide gp33 together with CpG-ODNs. In these experiments, B cells, potentially serving as CpG-ODN-activated antigen-presenting cells (APCs), were not required for induction of protective immunity since CpG-ODN-gp33-immunized B-cell-deficient mice were equally protected against challenge infection with both viruses. This finding suggested that macrophages and/or dendritic cells were sufficiently activated in vivo by CpG-ODNs to serve as potent APCs for the induction of naive T cells. Furthermore, treatment with CpG-ODN alone induced protection against infection with Listeria monocytogenes via antigen-independent activation of macrophages. These data suggest that CpG activation of macrophages and dendritic cells may provide a critical step in CpG-ODN adjuvant activity.

Adjuvants, Immunologic↗
PubMed2006

CpG oligodeoxynucleotide prolongs eosinophil survival through activation of contaminating B cells and plasmacytoid dendritic cells in vitro.

BACKGROUND: In our previous study, oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODNs) significantly prolonged eosinophil survival without inducing active release of eosinophil-derived neurotoxin or interleukin 8. In addition, this survival-promoting activity was nuclear factor-kappaB dependent. However, some eosinophil preparations from different donors hardly responded to CpG ODNs at all. To clarify why CpG ODN-induced nuclear factor-kB activation in eosinophils does not cause eosinophil-derived neurotoxin or interleukin 8 release and why the survival-promoting activity of CpG ODNs was not found in some eosinophil preparations, we determined the effect of extensive removal of contaminating B cells and plasmacytoid dendritic cells from human eosinophil preparations. METHODS: Eosinophils were purified from the peripheral blood of healthy or slightly allergic donors by gradient sedimentation and negative selection with anti-CD16 alone or a combination of anti-CD16, anti-CD19 and anti-blood dendritic cell antigen 4 (BDCA4) immunomagnetic beads. Eosinophil survival was measured with FITC-conjugated annexin V and propidium iodide by FACS after incubation with synthetic CpG 2006(CpG-B), CpG 2216 (CpG-A) or their GpC control ODNs for 24 h. RESULTS: The addition of anti-CD19 and anti-BDCA4 immunomagnetic beads reduced the number of contaminating CD19+ cells and CD123+ BDCA2+ cells in eosinophil preparations. CpG 2006 and CpG 2216, but not their GpC control ODNs, significantly prolonged survival of eosinophils purified with anti-CD16 immunomagnetic beads alone but not eosinophils purified with a combination of anti-CD16, anti-CD19 and anti-BDCA4 beads. CONCLUSIONS: These results strongly suggest that contaminating B cells or plasmacytoid dendritic cells in eosinophil preparations critically regulate CpG ODN-mediated prolongation of eosinophil survival and that CpG ODNs do not activate eosinophils directly.

Adjuvants, Immunologic↗
PubMed2005

Limited effect of CpG ODN in preventing type 1 diabetes in NOD mice.

Type 1 diabetes is considered as Th1 cell mediated autoimmune disease and the suppression of Th1 cells or the activation of Th2 cells has been regarded as a plausible immunologic intervention for the prevention of type 1 diabetogenesis in a rodent model. CpG ODN is an immunostimulatory sequence primarily present in bacterial DNA, viral DNA and BCG. CpG ODN is conventionally classified as a Th1 cell activator, which has been clinically applied to cancer, allergy and infectious disease. Recently, there was a promising report of that CpG ODN administration suppressed the development of type 1 diabetes in NOD mice by inducing Th2 cell mediated cytokine. However, the antidiabetogenic effect of CpG ODN on NOD mice is controversial. Thus, two studies were serially undertaken with various kinds of CpG motif to find a more optimal sequence and administration method. In the first study, CpG ODN was vaccinated four times and pancreatic inflammation and the quantity of serum insulin subsequently evaluated. In the second study, the amounts of IFN gamma and IL-4 in sera were measured as representative cytokines of Th1 and Th2 cells, respectively. As a result, vaccination or continuous injection of CpG ODN failed to show a preventive effect on type 1 diabetogenesis in NOD mice. Structural differences of CpG ODN also had no affect on the result. CpG ODN also consistently showed affect on the pancreatic pathology. The productions of IFN gamma and IL-4 were detected only in the K and D type CpG ODN administration groups. Comparison of the two cytokines leads to the conclusion that CpG ODN generated a Th1-weighted response in both study groups. It was assumed that CpG ODN failed to produce Th2-weighted cytokine milieu, which can overcome the genetically determined phenotype of NOD mice. Given these results, it was concluded that the immunotherapeutic application of CpG ODN on Type 1 diabetes had clear limitations.

Animals↗
PubMed2002

Methylation patterns of the human beta-glucuronidase gene locus: boundaries of methylation and general implications for frequent point mutations at CpG dinucleotides.

Methylation of CpG islands spanning promoter regions is associated with control of gene expression, although it is unclear what mechanisms define the boundaries between methylated and unmethylated regions in the genome. Methylation of genomic DNA in mammals also affects the frequency of inherited diseases by predisposing them to CpG mutations. To gain insight into these issues, we investigated patterns of cytosine methylation on almost the entire beta-glucuronidase gene (GUSB) from normal leukocyte DNAs by bisulfite genomic sequencing. We mapped the boundaries of methylation that flank the 5'- and 3'-ends of the CpG island region, and correlated methylation status with transitional mutations at CpG sites. GenBank sequence analyses showed that the CpG island of human GUSB is juxtaposed with multiple Alu repeats and also includes multiple Sp1 sites upstream and downstream of the transcription start, which has been suggested to prevent CpG islands from becoming methylated. We show that cytosine methylation is extensive across the entire gene except for CpG sites in the proximal promoter region, exon 1, and part of intron 1; the unmethylated CpG island is embedded between densely methylated flanking regions containing multiple Alu repeats; a sharp boundary separates the methylated and unmethylated regions of the 5'-flank of the CpG island, but a gradual change in methylation density over 1.0 kb is observed in the 3'-flank of the CpG island; boundaries of the 5'-end and 3'-end of the CpG island contain multiple Sp1 sites in addition to Alu repeats; methylation in both strands is symmetrical except at the boundary regions between methylated and unmethylated regions; and nonmethylation of exon 1 correlates with the absence of transitional mutations at CpG sites in exon 1.

3' Flanking Region↗
PubMed1999

CpG oligodeoxynucleotides do not require TH1 cytokines to prevent eosinophilic airway inflammation in a murine model of asthma.

BACKGROUND: Oligodeoxynucleotides (ODNs) containing the dinucleotide CpG in a specific sequence context (CpG-ODNs) have the ability to prevent the development of eosinophilic airway inflammation and bronchial hyperreactivity in a murine model of asthma. We have previously demonstrated that CpG-ODNs stimulate expression of the T(H1)-inducing cytokines IFN-gamma and IL-12 in a murine model of asthma and that this stimulation is associated with the protection against asthmatic inflammation. OBJECTIVE: The purpose of this study was to examine whether the protection conferred by CpG-ODNs in a schistosome egg-egg antigen murine model of asthma is dependent on the induction of IFN-gamma, IL-12, or both. METHODS: C57BL/6 mice were sensitized to schistosome eggs in the presence or absence of CpG-ODNs or control ODNs and then stimulated with soluble egg antigen in the airway. The protection offered by CpG-ODNs in these mice was compared with the protection induced by CpG-ODNs in IL-12 and IFN-gamma knockout mice and in mice treated with anticytokine blocking antibodies. Double-knockout mice (IL-12/IFN-gamma) were also generated and used in these studies. Determinations included airway eosinophilic inflammation and bronchial hyperreactivity to inhaled methacholine. RESULTS: We found that CpG-ODNs confer protection against both airway eosinophilia and bronchial hyperreactivity in the absence of IFN-gamma or IL-12 or in the presence of both cytokines together. However, in the absence of either IL-12 or IFN-gamma, mice require 10 times as much CpG-ODNs to be protected against the induction of airway eosinophilia. The T(H2) cytokines IL-4 and IL-5 were reduced in all of the CpG-treated mice, although less in the absence of IL-12 and IFN-gamma. CONCLUSION: These data indicate that CpG-ODNs prevent the generation of T(H2)-like immune responses by multiple mechanisms, which involve, but do not require, IL-12 and IFN-gamma. A direct suppressive effect of CpG-ODNs on T(H2) responses is suggested by their reduction in IFN-gamma and IL-12 knockout mice.

Animals↗
PubMed2001

Gene-associated CpG islands in plants as revealed by analyses of genomic sequences.

We screened plant genome sequences, primarily from rice and Arabidopsis thaliana, for CpG islands, and identified DNA segments rich in CpG dinucleotides within these sequences. These CpG-rich clusters appeared in the analysed sequences as discrete peaks and occurred at the frequencies of one per 4.7 kb in rice and one per 4.0 kb in A. thaliana. In rice and A. thaliana, most of the CpG-rich clusters were associated with genes, which suggests that these clusters are useful landmarks in genome sequences for identifying genes in plants with small genomes. In contrast, in plants with larger genomes, only a few of the clusters were associated with genes. These plant CpG-rich clusters satisfied the criteria used for identifying human CpG islands, which suggests that these CpG clusters may be regarded as plant CpG islands. The position of each island relative to the 5'-end of its associated gene varied considerably. Genes in the analysed sequences were grouped into five classes according to the position of the CpG islands within their associated genes. A large proportion of the genes belonged to one of two classes, in which a CpG island occurred near the 5'-end of the gene or covered the whole gene region. The position of a plant CpG island within its associated gene appeared to be related to the extent of tissue-specific expression of the gene; the CpG islands of most of the widely expressed rice genes occurred near the 5'-end of the genes.

Arabidopsis↗
PubMed2001

The enhanced effect of a hexameric deoxyriboguanosine run conjugation to CpG oligodeoxynucleotides on protection against allergic asthma.

BACKGROUND: Oligodeoxynucleotides containing a CpG motif (CpG ODNs), as potent inducers of T(H)1 immunity, are considered promising candidates for immune modulation in asthma. We have previously demonstrated that conjugation of a hexameric deoxyriboguanosine run to the 3' terminus (3' dG(6)-run) of phosphodiester (PE) CpG ODNs enhanced their immuno-stimulatory activities in vitro. OBJECTIVE: This study aimed to evaluate the effect of a 3' dG(6)-run conjugation to PE or phosphorothioate (PS) CpG ODNs on protection against murine allergic asthma in vivo. METHODS: Balb/c mice were sensitized to ovalbumin by intraperitoneal injection with or without CpG ODNs (PS CpG ODNs, PE CpG ODNs, and those with 3' dG(6)-run) and subsequently challenged with ovalbumin. We evaluated airway hyperresponsiveness, eosinophil proportion in bronchoalveolar lavage fluid, airway inflammation, and ovalbumin-specific antibody responses. RESULTS: The conjugation of a 3' dG(6)-run to PE CpG ODNs enhanced the production of IFN-gamma from ovalbumin-specific T(H) cells and prevented the development of asthma in terms of airway hyperresponsiveness, airway eosinophilia, and ovalbumin-specific IgE responses; these effects were comparable to those of PS CpG ODNs. Enhanced effects of the 3' dG(6)-run were also observed in PS CpG ODNs, though they were lower than those in PE CpG ODNs. CONCLUSION: This study suggests that conjugation of a 3' dG(6)-run to CpG ODNs might provide an effective method for immune modulation of allergic asthma.

Animals↗
PubMed1998

Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs.

Unmethylated CpG dinucleotides in particular base contexts (CpG-S motifs) are relatively common in bacterial DNA but are rare in vertebrate DNA. B cells and monocytes have the ability to detect such CpG-S motifs that trigger innate immune defenses with production of Th1-like cytokines. Despite comparable levels of unmethylated CpG dinucleotides, DNA from serotype 12 adenovirus is immune-stimulatory, but serotype 2 is nonstimulatory and can even inhibit activation by bacterial DNA. In type 12 genomes, the distribution of CpG-flanking bases is similar to that predicted by chance. However, in type 2 adenoviral DNA the immune stimulatory CpG-S motifs are outnumbered by a 15- to 30-fold excess of CpG dinucleotides in clusters of direct repeats or with a C on the 5' side or a G on the 3' side. Synthetic oligodeoxynucleotides containing these putative neutralizing (CpG-N) motifs block immune activation by CpG-S motifs in vitro and in vivo. Eliminating 52 of the 134 CpG-N motifs present in a DNA vaccine markedly enhanced its Th1-like function in vivo, which was increased further by the addition of CpG-S motifs. Thus, depending on the CpG motif, prokaryotic DNA can be either immune-stimulatory or neutralizing. These results have important implications for understanding microbial pathogenesis and molecular evolution and for the clinical development of DNA vaccines and gene therapy vectors.

Adenoviridae↗
PubMed2003

CpG oligodeoxynucleotides modulate the osteoclastogenic activity of osteoblasts via Toll-like receptor 9.

Regulation of osteoclastogenesis by lipopolysaccharide (LPS) is mediated via its interactions with toll-like receptor 4 (TLR4) on both osteoclast- and osteoblast-lineage cells. We have recently demonstrated that CpG oligodeoxynucleotides (CpG ODNs), known to mimic bacterial DNA, modulate osteoclastogenesis via interactions with osteoclast precursors. In the present study we characterize the interactions of CpG ODNs with osteoblasts, in comparison with LPS. We find that, similar to LPS, CpG ODNs modulate osteoclastogenesis in bone marrow cell/osteoblast co-cultures, although in a somewhat different pattern. Osteoblasts express receptors for both LPS and CpG ODN (TLR4 and TLR9, respectively). The osteoblastic TLR9 transmits signals into the cell as demonstrated by NFkappaB activation as well as by extracellular-regulated kinase (ERK) and p38 phosphorylation. Similar to LPS, CpG ODN increases in osteoblasts the expression of tumor necrosis factor (TNF)-alpha and macrophage-colony stimulating factor (M-CSF). The two TLR ligands do not affect osteoprotegerin expression in osteoblasts. CpG ODN does not significantly affect receptor activator of NFkappaB ligand (RANKL) expression, in contrast to LPS, which induces the expression of this molecule. In the co-cultures CpG ODN induces RANKL expression in osteoblasts as a result of the more efficient TNF-alpha induction. CpG ODN activity (modulation of osteoclastogenesis, gene expression, ERK and p38 phosphorylation, and nuclear translocation of NFkappaB) is specific, because the control oligodeoxynucleotide, not containing CpG, is inactive. Furthermore, these effects (unlike the LPS effects) are inhibited by chloroquine, suggesting a requirement for endosomal maturation/acidification, the classic CpG ODN mode of action. We conclude that CpG ODN, upon TLR9 ligation, induces osteoblasts osteoclastogenic activity.

Animals↗
PubMed2004

CpG oligodeoxynucleotides activate HIV replication in latently infected human T cells.

CpG oligodeoxynucleotides (CpG ODNs) stimulate immune cells via the Toll-like receptor 9 (TLR9). In this study, we have investigated the effects of CpG ODNs on latent human immunodeficiency virus (HIV) infection in human T cells. Treatment of the latently infected T cell line ACH-2 with CpG ODNs 2006 or 2040 stimulated HIV replication, whereas no effects were evident when ODNs without the CpG motif were used. CpG-induced virus reactivation was blocked by chloroquine, indicating the involvement of TLR9. In contrast to the responsiveness of ACH-2 cells, CpG ODNs failed to activate HIV provirus in the latently infected Jurkat clone J1.1. We also studied the effects of CpG ODNs on productive HIV infection and found enhancement of viral replication in A3.01 T cells, whereas again no stimulating effects were observed in Jurkat T cells. CpG ODN treatment activated NF-kappaB in ACH-2 cells, which was similarly triggered in uninfected A3.01 T cells following exposure to CpG ODNs, indicating that TLR9-induced signal transduction was not dependent on proviral infection. Our study demonstrates that CpG ODNs directly trigger the activation of NF-kappaB and reactivation of latent HIV in human T cells. Our results point to a novel role for CpG ODNs as stimulators of HIV replication and open new avenues to eradicate the latent viral reservoirs in HIV-infected patients treated with antiretroviral therapy.

Amino Acid Motifs↗
PubMed2005

CpG oligodeoxynucleotide protection in polymicrobial sepsis is dependent on interleukin-17.

CpG oligodeoxynucleotides (ODNs) may prevent mortality from infection. We have identified a therapeutic benefit in treating sepsis with phosphorothioate ODN sequences containing the CpG motif. Sepsis was induced in rats by cecal ligation and puncture (CLP), and treatment with CpG ODNs reduced sepsis mortality from 80% to 15% during a 108-h period. Protection from mortality was dose dependent. Bacterial load in peritoneal fluid was reduced in CpG ODN-treated versus non-CpG ODN-treated rats after CLP. Lung injury, as determined by total myeloperoxidase activity, was also reduced in CpG ODN-treated versus non-CpG ODN-treated rats after CLP. Indirect evidence suggests that CpG-induced expression of interleukin (IL)-23 as levels of p40--but not p35--were significantly increased in both plasma and peritoneal lavage fluid in CpG ODN-treated versus non-CpG ODN-treated rats 24 h after CLP. Anti-IL-17 antibody inhibited the CpG-mediated prevention of mortality. These data suggest that IL-17 may mediate CpG-inducible host defenses during intraabdominal sepsis.

Animals↗
PubMed2004

An evaluation of new criteria for CpG islands in the human genome as gene markers.

MOTIVATION: Recently, more stringent criteria for CpG islands have been introduced to exclude Alu repeats, thereby enabling a higher proportion of CpG islands associating with genes to be identified. Using these new criteria, several types of associations between CpG islands and genes were investigated to further establish the importance of CpG islands as gene markers. RESULTS: The CpG islands were searched by CpGIE, a java software program developed for CpG island identification. CpGIE was advanced in identification accuracy compared with other tools. According to our results, about 70% of the identified CpG islands were associating with the human genes and over half of them are in the promoters. Furthermore, the investigation of genes in the confirmed gene model showed that 56% of them had a CpG island overlapping the transcription start sites. In comparison, the new criteria were found capable of filtering a large fraction of Alu repeats that was identified as CpG islands by the generally accepted criteria within the genes, but very few CpG islands associating with the promoters were affected. The genes in the predicted gene model were not obviously associated with CpG islands, suggesting that CpG islands can be used to evaluate the accuracy of gene annotation. AVAILABILITY: http://bioinfo.hku.hk/cpgieintro

Algorithms↗
PubMed2004

Gene-Ontology analysis reveals association of tissue-specific 5' CpG-island genes with development and embryogenesis.

A key open question in the understanding of the biology of DNA methylation relates to the origin and function of CpG islands, stretches of GC-rich and relatively CpG-rich DNA sequence that often colocalize with promoter regions. All housekeeping, but also a substantial minority of tissue-specific genes are associated with the CpG islands. Limited experimental evidence suggests that CpG islands are associated with promoters or replication origins active during early development. Although this hypothesis is attractive for widely expressed genes, which would be expected to be expressed during early development, many tissue-specific genes also contain CpG islands. In this work, we used a genome-wide Gene-Ontology (GO)-based approach to analyze associations between GO terms and the presence of 5' CpG islands in human Reference Sequence (RefSeq) genes. We found that 19 of the 3849 GO terms with at least one annotated human sequence showed a highly significant association with the likelihood of 5' CpG islands being present in genes annotated to that term. In particular, the term 'development' showed a highly significantly increased proportion of 5' CpG island genes. The overrepresentation of 5' CpG island genes was even more significant for tissue-specific RefSeqs annotated to development as well as many of its descendent terms. In addition, the proportion of expressed sequence tags from embryonic libraries amongst tissue-specific genes was twice as high for RefSeqs with 5' CpG islands as for those without CpG islands. These results provide strong support for previous speculations that early embryonic expression is associated with CpG islands.

Animals↗
PubMed2003

The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets.

Oligodeoxynucleotides containing unmethylated CpG motifs (CpG DNAs) can function as powerful immune adjuvants by activating APC. Compared with conventional phosphorothioate-backbone CpG DNAs, another type of CpG DNAs, called an A or D type (A/D-type), possesses higher ability to induce IFN-alpha production. Conventional CpG DNAs can exert their activity through Toll-like receptor 9 (TLR9) signaling, which depends on a cytoplasmic adapter, MyD88. However, it remains unknown how A/D-type CpG DNAs exhibit their immunostimulatory function. In this study we have investigated murine dendritic cell (DC) responses to these two distinct CpG DNAs. Not only splenic, but also in vitro bone marrow-derived, DCs could produce larger amounts of IFN-alpha in response to A/D-type CpG DNAs compared with conventional CpG DNAs. This IFN-alpha production was mainly due to the B220(+) DC subset. On the other hand, the B220(-) DC subset responded similarly to both CpG DNAs in terms of costimulatory molecule up-regulation and IL-12 induction. IFN-alpha, but not IL-12, induction was dependent on type I IFN. However, all activities of both CpG DNAs were abolished in TLR9- and MyD88-, but were retained in DNA-PKcs-deficient DCs. This study demonstrates that the TLR9-MyD88 signaling pathway is essential for all DC responses to both types of CpG DNAs.

Adaptor Proteins, Signal Transducing↗