T Cell-Independent, TLR-Induced IL-12p70 Production in Primary Human Monocytes

Bekeredjian‐Ding, Isabelle; Roth, Susanne; Gilles, Stefanie; Giese, Thomas; Ablasser, Andrea; Hornung, Veit; Endres, Stefan; Hartmann, Gunther

doi:10.4049/jimmunol.176.12.7438

Cited by 102 publications

(102 citation statements)

References 55 publications

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“…However, in our study we used macrophages, a cell type that is different from endothelial cells, which can explain the discrepancy. In cooperation with TLR4 signaling, TLR7/8 was shown recently to induce IL-12p70 synthesis in human monocytes, triggering a potent Th1 response before T cell help is established (51). However, consistent with our results that TLR2 had little effect on the early induction of IFN-␤, a potential IL-12p70 inducer (20), the combination of TLR2 and TLR7/8 signaling was found unable to induce IL-12p70 in human monocytes (51).…”

Section: Discussionsupporting

confidence: 67%

“…In cooperation with TLR4 signaling, TLR7/8 was shown recently to induce IL-12p70 synthesis in human monocytes, triggering a potent Th1 response before T cell help is established (51). However, consistent with our results that TLR2 had little effect on the early induction of IFN-␤, a potential IL-12p70 inducer (20), the combination of TLR2 and TLR7/8 signaling was found unable to induce IL-12p70 in human monocytes (51). Interestingly, we observed that TLR7 was essential for the early induction of IFN-␤ (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Identification of Signaling Pathways in Macrophage Exposed to Porphyromonas gingivalis or to Its Purified Cell Wall Components

Zhou

Amar

2007

The Journal of Immunology

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Porphyromonas gingivalis (P. gingivalis) can trigger an inflammatory condition leading to the destruction of periodontal tissues. However P. gingivalis LPS and its fimbriae (FimA) play different roles compared with the live bacteria in the context of intracellular molecule induction and cytokine secretion. To elucidate whether this difference results from different signaling pathways in host immune response to P. gingivalis, its LPS, or its FimA, we examined gene expression profile of human macrophages exposed to P. gingivalis, its LPS, or its FimA. A comparison of gene expression resulted in the identification of three distinct groups of expressed genes. Furthermore, computer-assisted promoter analysis of a subset of each group of differentially regulated genes revealed four putative transcriptional regulation models that associate with transcription factors NFκB, IRF7, and KLF4. Using gene knockout mice and siRNA to silence mouse genes, we showed that both TLR2 and TLR7 are essential for the induction of NFκB-containing genes and NFκB-IFN-sensitive response element (ISRE) cocontaining genes by either P. gingivalis or its purified components. The gene induction via either TLR2 or TLR7 is dependent on both MyD88 and p38 MAPK. However, the unique induction of IFN-β by P. gingivalis LPS requires TLR7 and IFNαβR cosignaling, and the induction of ISRE-containing gene is dependent on the activation of IFN-β autocrine loop. Taken together, these data demonstrate that P. gingivalis and its components induce NFκB-containing genes through either TLR2- or TLR7-MyD88-p38 MAPK pathway, while P. gingivalis LPS uniquely induces ISRE-containing genes, which requires IFNαβR signaling involving IRF7, KLF4, and pY701 STAT1.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Identification of Signaling Pathways in Macrophage Exposed to Porphyromonas gingivalis or to Its Purified Cell Wall Components

Zhou

Amar

2007

The Journal of Immunology

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“…In fact, we identified monocytes as the major source of IL-12p70 upon ssRNA stimulation within PBMC. The exclusive expression of TLR8 in monocytes (24,30), sensitivity toward inhibition by chloroquine, and siRNAmediated knock-down experiments support the concept of TLR8-dependent recognition of RNA-pLa complexes to be responsible for massive IL-12p70 induction. This previously unappreciated capability of monocytes to produce large amounts of IFN-␣ and IL12p70 can be used to establish and maintain potent Th1 immune responses.…”

Section: Discussionmentioning

confidence: 69%

“…So far DC are thought to represent the major source of IL-12p70. However, IL-12p70 production within DC is known to be tightly controlled, usually requiring multiple stimuli to synergize and to induce its expression (30). In fact, we identified monocytes as the major source of IL-12p70 upon ssRNA stimulation within PBMC.…”

Section: Discussionmentioning

confidence: 84%

Selection of Molecular Structure and Delivery of RNA Oligonucleotides to Activate TLR7 versus TLR8 and to Induce High Amounts of IL-12p70 in Primary Human Monocytes

Ablasser

Poeck

Anz

et al. 2009

The Journal of Immunology

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Detection of non-self RNA by TLRs within endosomes and by retinoic acid-inducible gene I (RIG-I)-like helicases in the cytosol is central to mammalian antiviral immunity. In this study, we used pathway-specific agonists and targeted delivery to address RNA immunorecognition in primary human immune cells. Within PBMC, plasmacytoid dendritic cells (pDC) and monocytes were found to be responsible for IFN-α production upon immunorecognition of RNA. The mechanisms of RNA recognition in pDC and monocytes were distinct. In pDC, recognition of ssRNA and dsRNA oligonucleotides was TLR7-dependent, whereas a 5′ triphosphate moiety (RIG-I ligand activity) had no major contribution to IFN-α production. In monocytes, the response to RNA oligonucleotides was mediated by either TLR8 or RIG-I. TLR8 was responsible for IL-12 induction upon endosomal delivery of ssRNA oligonucleotides and RIG-I was responsible for IFN-α production upon delivery of 5′ triphosphate RNA into the cytosol. In conclusion, the dissection of these pathways by selecting the appropriate structure and delivery of RNA reveals pDC as major producer of IFN-α upon TLR-mediated stimulation and monocytes as major producer of IFN-α upon RIG-I-mediated stimulation. Furthermore, our results uncover the potential of monocytes to function as major producers of IL-12p70, a key Th1 cytokine classically ascribed to myeloid dendritic cells that cannot be induced by CpG oligonucleotides in the human system.

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“…1A). In concert with the role of TLR8 in the production of NF-κB-dependent cytokines (33)(34)(35), IRS957 also caused a significant decrease in secretion of TNF-α, IL-6, and IL-10 by Bb-infected monocytes (Fig. 1B).…”

mentioning

confidence: 97%

Phagosomal signaling byBorrelia burgdorferiin human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β

Cervantes¹,

Dunham-Ems²,

Vake³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

140

149

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Phagocytosed Borrelia burgdorferi (Bb) induces inflammatory signals that differ both quantitatively and qualitatively from those generated by spirochetal lipoproteins interacting with Toll-like receptor (TLR) 1/2 on the surface of human monocytes. Of particular significance, and in contrast to lipoproteins, internalized spirochetes induce transcription of IFN-β. Using inhibitory immunoregulatory DNA sequences (IRSs) specific to TLR7, TLR8, and TLR9, we show that the TLR8 inhibitor IRS957 significantly diminishes production of TNF-α, IL-6, and IL-10 and completely abrogates transcription of IFN-β in Bb-stimulated monocytes. We demonstrate that live Bb induces transcription of TLR2 and TLR8, whereas IRS957 interferes with their transcriptional regulation. Using confocal and epifluorescence microscopy, we show that baseline TLR expression in unstimulated monocytes is greater for TLR2 than for TLR8, whereas expression of both TLRs increases significantly upon stimulation with live spirochetes. By confocal microscopy, we show that TLR2 colocalization with Bb coincides with binding, uptake, and formation of the phagosomal vacuole, whereas recruitment of both TLR2 and TLR8 overlaps with degradation of the spirochete. We provide evidence that IFN regulatory factor (IRF) 7 is translocated into the nucleus of Bb-infected monocytes, suggesting its activation through phosphorylation. Taken together, these findings indicate that the phagosome is an efficient platform for the recognition of diverse ligands; in the case of Bb, phagosomal signaling involves a cooperative interaction between TLR2 and TLR8 in pro-and antiinflammatory cytokine responses, whereas TLR8 is solely responsible for IRF7-mediated induction of IFN-β.Lyme disease | endosomal receptors | type I interferons | phagocytosis

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T Cell-Independent, TLR-Induced IL-12p70 Production in Primary Human Monocytes

Cited by 102 publications

References 55 publications

Identification of Signaling Pathways in Macrophage Exposed to Porphyromonas gingivalis or to Its Purified Cell Wall Components

Identification of Signaling Pathways in Macrophage Exposed to Porphyromonas gingivalis or to Its Purified Cell Wall Components

Selection of Molecular Structure and Delivery of RNA Oligonucleotides to Activate TLR7 versus TLR8 and to Induce High Amounts of IL-12p70 in Primary Human Monocytes

Phagosomal signaling byBorrelia burgdorferiin human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β

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