Signal transduction pathways mediated by the interaction of CpG DNA with Toll-like receptor 9

Takeshita, Fumihiko; Gürsel, İhsan; Ishii, Ken J.; Suzuki, Koichi; Gürsel, Mayda; Klinman, Dennis M.

doi:10.1016/j.smim.2003.10.009

Cited by 165 publications

(144 citation statements)

References 42 publications

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“…PI3K/Akt activation could be an alternative pathway to the IL-1R-associated kinase/IKK/NF-B pathway, leading to independent modulation of Bcl-2 family proteins (52). Increased levels of Mcl-1 have been implicated in PMN survival induced by proinflammatory cytokines such as GM-CSF, IL-1, TNF-␣, and IL-15 (12,33,53,54).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-κB Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad

François

Benna

Dang

et al. 2005

The Journal of Immunology

208

223

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Using flow cytometry, we investigated the effect of TLR agonists on human polymorphonuclear neutrophil (PMN) apoptosis in whole blood. LPS (TLR4), peptidoglycan (TLR2), R-848 (TLR7/8), and CpG-DNA (TLR9) were equally effective at delaying spontaneous apoptosis of PMN, while PamCSK4 (TLR1/2), macrophage-activating lipopeptide-2 (TLR2/6), flagellin (TLR5), and loxoribine (TLR7) were less effective or inactive. TLR agonists found to delay apoptosis also extended the functional life span of PMN. Analysis of signaling pathways revealed that the antiapoptotic effect of TLR agonists required NF-κB and PI3K activation. Furthermore, analysis of intact cells by flow cytometry showed that TLR agonists delaying PMN apoptosis increased phosphorylation of Akt, a major target of PI3K. This effect was associated with a PI3K-dependent increase in heat shock protein 27 phosphorylation, which has been reported to play a key role in PMN survival. Finally, the TLR-induced delay in PMN apoptosis was associated with increased levels of Mcl-1 and A1, which are antiapoptotic members of the Bcl-2 family. These effects were reversed by PI3K and NF-κB inhibitors, respectively. TLR activation also led to PI3K-dependent phosphorylation of the proapoptotic protein Bad. Taken together, our results strongly suggest a role of NF-κB and PI3K in TLR-induced PMN survival, leading to modulation of Bcl-2 family molecules.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-κB Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad

François

Benna

Dang

et al. 2005

The Journal of Immunology

208

223

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“…Although review of the field of vaccine adjuvant development is outside the scope of this review, it is critical to note that rapid advances in the field of dendritic cell biology, B cell immunoregulation and Toll-like receptor signaling have provided important new insights that the HIV-1 vaccine field needs to access for design of optimal HIV-1 vaccines [195][196][197][198][199][200][201][202][203].…”

Section: Adjuvant Design For Hiv-1 Vaccinesmentioning

confidence: 99%

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Haynes¹,

Montefiori²

2006

Expert Review of Vaccines

103

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Neutralizing antibody induction is a key feature of many effective vaccines and is the only immune response that has proven to be capable of completely blocking AIDS virus infection in animal models. Unfortunately, the extensive genetic variability and complex immune-evasion strategies of HIV-1 have thwarted all attempts to date at eliciting an effective neutralizing antibody response with candidate HIV-1 vaccine immunogens. Recent advances in our understanding of how these evasion strategies operate, coupled with growing progress in unravelling the structure and immunobiology of the viral envelope glycoproteins, are contributing to novel immunogen designs to overcome the many barriers to inducing protective antibodies against HIV-1. Keywordsantiretroviral therapy; HIV-1; host cell fusion; immunogen; neutralizing antibody induction Development of a safe, practical and effective HIV-1 vaccine is one of the highest priorities of the global scientific community [1,2]. Although antiretroviral therapy (ART) has dramatically prolonged the lives of HIV-1 infected patients, ART is not yet routinely available in developing countries, and the global rate of spread of HIV-1 continues unabated. If no effective AIDS vaccine is developed by 2010, the number of people infected world-wide with HIV-1 could exceed 60 million [3].In spite of more than 20 years of research, the types of immune responses needed to protect an immunized individual from HIV-1 infection are not known. Its is known that CD8 + cytotoxic T-cell responses can control HIV-1 replication to varying degrees in acute HIV-1 infection (AHI) [4,5], and when induced by immunogens, can control viral set point after simian immunodeficiancy virus (SIV) or simian HIV (SHIV) challenges in non-human primates [4]. Strong proliferative CD4 + T-cell responses to HIV-1 proteins have been demonstrated to correlate well with immune control of HIV-1 viral load [5]. Therefore, it is highly desirable for an HIV-1 vaccine co induce robust CD4 + and CD8 + T-cell responses in order to control virus replication and reduce the likelihood of subsequent transmission [4][5][6][7]. The potential for complete ('sterilizing') immunity from HIV-1 infection may depend on the presence of pre-existing neutralizing antibodies. We know that neutralizing antibodies can prevent the acquisition of AIDS virus infection after intravenous, vaginal, rectal and oral virus challenge in nonhuman primates [8][9][10][11][12]. This level of protection is highly attractive for a vaccine against a virus, such as HIV-1, which integrates genetically and forms latent viral reservoirs soon after infection. However, the diversity of transmitted HIV-1 genetic variants and the relative resistance of the majority of HIV-1 primary isolates to most types of inducible neutralizing antibodies have posed major hurdles to current vaccine efforts. Furthermore, the few rare broadly reactive neutralizing monoclonal antibodies (mAbs) that have been isolated from HIV-1 infected patients represent species of antibodies that...

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“…Microorganisms (prokaryotes) and tumor cells share a common feature: both contain unmethylated CpG motifs at a higher frequency than eukaryotes and normal cells, respectively. The innate immune system detects unmethylated CpG motifs using TLR-9 (26). The release of unmethylated CpG DNA during an infection provides a danger signal to the innate immune system, triggering a protective immune response that improves the ability of the host to eliminate the pathogen (27).…”

Section: Org Downloaded Frommentioning

confidence: 99%

Circulating Methylated DNA: A New Generation of Tumor Markers

Widschwendter

Menon

2006

Clinical Cancer Research

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Signal transduction pathways mediated by the interaction of CpG DNA with Toll-like receptor 9

Cited by 165 publications

References 42 publications

Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-κB Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad

Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-κB Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Circulating Methylated DNA: A New Generation of Tumor Markers

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