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These results demonstrate that TLR induce IFN-alpha or IFN-beta responses by activating distinct IRF, depending on the TLR ligand and the cell type.</csml:comment>
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MyD88 recruits various signaling molecules, such as IRAK4 (IL-1R-associated kinase 4), IRAK1 and TRAF6 (TNFR-associated factor 6), which leads to activation and nuclear translocation of the transcription factor NF-kappaB that induces pro-inflammatory cytokine genes.</csml:comment>
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MyD88 recruits various signaling molecules, such as IRAK4 (IL-1R-associated kinase 4), IRAK1 and TRAF6 (TNFR-associated factor 6), which leads to activation and nuclear translocation of the transcription factor NF-kappaB that induces pro-inflammatory cytokine genes.</csml:comment>
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<csml:comment type="text">PMID: 17273997
MyD88 recruits various signaling molecules, such as IRAK4 (IL-1R-associated kinase 4), IRAK1 and TRAF6 (TNFR-associated factor 6), which leads to activation and nuclear translocation of the transcription factor NF-kappaB that induces pro-inflammatory cytokine genes.</csml:comment>
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<csml:comment type="text">PMID: 17273997
MyD88 also recruits IRF-5 and triggers a TRAF6 signaling pathway that leads to activation of NF-kappaB.</csml:comment>
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MyD88 recruits various signaling molecules, such as IRAK4 (IL-1R-associated kinase 4), IRAK1 and TRAF6 (TNFR-associated factor 6), which leads to activation and nuclear translocation of the transcription factor NF-kappaB that induces pro-inflammatory cytokine genes.</csml:comment>
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<csml:comment type="text">PMID: 17273997
The simultaneous activation and subsequent nuclear translocation of IRF and NF-kappaB allows all these transcription factors to bind at the same time to certain gene promoters, providing a tremendous enhancement of gene induction.</csml:comment>
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The simultaneous activation and subsequent nuclear translocation of IRF and NF-kappaB allows all these transcription factors to bind at the same time to certain gene promoters, providing a tremendous enhancement of gene induction.</csml:comment>
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<csml:comment type="text">PMID: 17273997
MyD88 recruits various signaling molecules, such as IRAK4 (IL-1R-associated kinase 4), IRAK1 and TRAF6 (TNFR-associated factor 6), which leads to activation and nuclear translocation of the transcription factor NF-kappaB that induces pro-inflammatory cytokine genes.

PMID: 17273997
Both NF-kappaB and IRF-5 induce transcription of pro-inflammatory cytokine genes (TNF-alpha, IL-6, IL-12p40).</csml:comment>
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<csml:comment type="text">PMID: 17273997
MyD88 recruits various signaling molecules, such as IRAK4 (IL-1R-associated kinase 4), IRAK1 and TRAF6 (TNFR-associated factor 6), which leads to activation and nuclear translocation of the transcription factor NF-kappaB that induces pro-inflammatory cytokine genes.

PMID: 17273997
Both NF-kappaB and IRF-5 induce transcription of pro-inflammatory cytokine genes (TNF-alpha, IL-6, IL-12p40).</csml:comment>
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<csml:comment type="text">PMID: 17273997
MyD88 recruits various signaling molecules, such as IRAK4 (IL-1R-associated kinase 4), IRAK1 and TRAF6 (TNFR-associated factor 6), which leads to activation and nuclear translocation of the transcription factor NF-kappaB that induces pro-inflammatory cytokine genes.

PMID: 17273997
Both NF-kappaB and IRF-5 induce transcription of pro-inflammatory cytokine genes (TNF-alpha, IL-6, IL-12p40).</csml:comment>
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<csml:comment type="text">PMID: 17273997
MyD88 recruits various signaling molecules, such as IRAK4 (IL-1R-associated kinase 4), IRAK1 and TRAF6 (TNFR-associated factor 6), which leads to activation and nuclear translocation of the transcription factor NF-kappaB that induces pro-inflammatory cytokine genes.</csml:comment>
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MyD88 recruits various signaling molecules, such as IRAK4 (IL-1R-associated kinase 4), IRAK1 and TRAF6 (TNFR-associated factor 6), which leads to activation and nuclear translocation of the transcription factor NF-kappaB that induces pro-inflammatory cytokine genes.</csml:comment>
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MyD88 recruits various signaling molecules, such as IRAK4 (IL-1R-associated kinase 4), IRAK1 and TRAF6 (TNFR-associated factor 6), which leads to activation and nuclear translocation of the transcription factor NF-kappaB that induces pro-inflammatory cytokine genes.</csml:comment>
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<csml:comment type="text">PMID: 17273997
In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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<csml:comment type="text">PMID: 17273997
In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.

PMID: 17273997, 16932750
It has previously been shown that phosphorylation is a critical event in IRF activation.</csml:comment>
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<csml:comment type="text">PMID: 17273997
In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.

PMID: 17273997, 16932750
It has previously been shown that phosphorylation is a critical event in IRF activation.</csml:comment>
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<csml:comment type="text">PMID: 17273997
The simultaneous activation and subsequent nuclear translocation of IRF and NF-kappaB allows all these transcription factors to bind at the same time to certain gene promoters, providing a tremendous enhancement of gene induction.

PMID: 17273997
PMID: 17273997
In all cells, the cytoplasmic sensors of dsRNA, MDA-5 and RIG-I, signal through the mitochondrial protein IPS-1 (interferon-beta promoter stimulator 1), which initiates a TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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The simultaneous activation and subsequent nuclear translocation of IRF and NF-kappaB allows all these transcription factors to bind at the same time to certain gene promoters, providing a tremendous enhancement of gene induction.

PMID: 17273997
In all cells, the cytoplasmic sensors of dsRNA, MDA-5 and RIG-I, signal through the mitochondrial protein IPS-1 (interferon-beta promoter stimulator 1), which initiates a TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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<csml:comment type="text">PMID: 17273997
In mDC, macrophages and other cells, TLR-3 and TLR-4 trigger a TRIF-&gt;TRAF3-&gt;TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.

PMID: 17273997
IRF-3 is a transcription factor that induces the IFN-beta gene and other genes, such as, IP-10 (IFN-gamma-induced protein-10.

PMID: 17273997
In all cells, the cytoplasmic sensors of dsRNA, MDA-5 and RIG-I, signal through the mitochondrial protein IPS-1 (interferon-beta promoter stimulator 1), which initiates a TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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IRF-3 is a transcription factor that induces the IFN-beta gene and other genes, such as, IP-10 (IFN-gamma-induced protein-10.
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In pDC, CpG-A trigger a TLR-9MyD88TRAF3IRF-7IFN-alpha/beta pathway.</csml:comment>
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In mDC and macrophages CpG-B trigger a TLR-9-&gt;MyD88-&gt;IRF-1-&gt;IFN-beta pathway.</csml:comment>
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In pDC, CpG-A trigger a TLR-9MyD88TRAF3IRF-7IFN-alpha/beta pathway.</csml:comment>
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In mDC and macrophages CpG-B trigger a TLR-9-&gt;MyD88-&gt;IRF-1-&gt;IFN-beta pathway.</csml:comment>
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<csml:comment type="text">PMID: 17273997
In fact, the authors demonstrate that this pathway requires IRF-1, which is recruited and activated by MyD88.

PMID: 17273997, 17018642
The study by Negishi et al. [6] demonstrates that IRF-1 interacts with the middle region of MyD88, overlapping with the region interacting with IRF-5 and IRF-4, but distinct from that binding IRF-7.</csml:comment>
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In pDC, CpG-A trigger a TLR-9-&gt;MyD88-&gt;TRAF3-&gt;IRF-7-&gt;IFN-alpha/beta pathway.</csml:comment>
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<csml:comment type="text">PMID: 17273997
In pDC, CpG-A trigger a TLR-9-&gt;MyD88-&gt;TRAF3-&gt;IRF-7-&gt;IFN-alpha/beta pathway.</csml:comment>
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<csml:comment type="text">PMID: 17273997
The IRF-1/3/7 and the NF-kappaB/IRF-5 pathways converge at the nuclear level to enhance the transcription of type I IFN genes or other genes containing IRF and NF-kappaB binding sites in their promoters (IL-12p35, iNOS).</csml:comment>
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In fact, the authors demonstrate that this pathway requires IRF-1, which is recruited and activated by MyD88.</csml:comment>
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The IRF-1/3/7 and the NF-kappaB/IRF-5 pathways converge at the nuclear level to enhance the transcription of type I IFN genes or other genes containing IRF and NF-kappaB binding sites in their promoters (IL-12p35, iNOS).</csml:comment>
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The IRF-1/3/7 and the NF-kappaB/IRF-5 pathways converge at the nuclear level to enhance the transcription of type I IFN genes or other genes containing IRF and NF-kappaB binding sites in their promoters (IL-12p35, iNOS).</csml:comment>
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<csml:comment type="text">PMID: 17273997
The IRF-1/3/7 and the NF-kappaB/IRF-5 pathways converge at the nuclear level to enhance the transcription of type I IFN genes or other genes containing IRF and NF-kappaB binding sites in their promoters (IL-12p35, iNOS).

PMID: 17273997
In contrast, when IFN-gamma signaling occurs together with TLR-9 engagement, IRF-1 is not only induced but is also activated and migrates rapidly into the nucleus to mediate efficient induction of IFN-beta, iNOS and IL-12p35.</csml:comment>
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<csml:comment type="text">PMID: 17273997
The IRF-1/3/7 and the NF-kappaB/IRF-5 pathways converge at the nuclear level to enhance the transcription of type I IFN genes or other genes containing IRF and NF-kappaB binding sites in their promoters (IL-12p35, iNOS).

PMID: 17273997
In contrast, when IFN-gamma signaling occurs together with TLR-9 engagement, IRF-1 is not only induced but is also activated and migrates rapidly into the nucleus to mediate efficient induction of IFN-beta, iNOS and IL-12p35.</csml:comment>
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Engagement of TLR-9 triggers not only the MyD88-&gt;IRF-1-&gt;IFN-beta pathway in mDC and the MyD88-&gt;IRF-7-&gt;IFN-alpha pathway in pDC, but also the MyD88-&gt;TRAF6 pathway that activates NF-kappaB in both cell types.</csml:comment>
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Engagement of TLR-9 triggers not only the MyD88-&gt;IRF-1-&gt;IFN-beta pathway in mDC and the MyD88-&gt;IRF-7-&gt;IFN-alpha pathway in pDC, but also the MyD88-&gt;TRAF6 pathway that activates NF-kappaB in both cell types.</csml:comment>
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<csml:comment type="text">PMID: 17273997
Engagement of TLR-9 triggers not only the MyD88-&gt;IRF-1-&gt;IFN-beta pathway in mDC and the MyD88-&gt;IRF-7-&gt;IFN-alpha pathway in pDC, but also the MyD88-&gt;TRAF6 pathway that activates NF-kappaB in both cell types.</csml:comment>
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<csml:comments>
<csml:comment type="text">PMID: 17273997
IRF-1 and IRF-7 are recruited and activated through MyD88, which simultaneously triggers a parallel signaling pathway for NF-kappaB and IRF-5 activation and secretion of proinflammatory cytokines.

PMID: 17273997, 16932750
Simultaneous activation of IRF-7 by viral infection leads to IRF-7-mediated induction of IFN-alpha.</csml:comment>
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<csml:parameter key="coefficient1" value="0.1"/>
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<csml:comments>
<csml:comment type="text">PMID: 17273997
The IRF-1/3/7 and the NF-kappaB/IRF-5 pathways converge at the nuclear level to enhance the transcription of type I IFN genes or other genes containing IRF and NF-kappaB binding sites in their promoters (IL-12p35, iNOS).</csml:comment>
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<csml:comment type="text">PMID: 17273997
The IRF-1/3/7 and the NF-kappaB/IRF-5 pathways converge at the nuclear level to enhance the transcription of type I IFN genes or other genes containing IRF and NF-kappaB binding sites in their promoters (IL-12p35, iNOS).</csml:comment>
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<csml:comment type="text">PMID: 17273997
The IRF-1/3/7 and the NF-kappaB/IRF-5 pathways converge at the nuclear level to enhance the transcription of type I IFN genes or other genes containing IRF and NF-kappaB binding sites in their promoters (IL-12p35, iNOS).</csml:comment>
</csml:comments>
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<csml:connector id="c128" name="c128" refID="e66" type="cso30:c:InputAssociation">
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<csml:comments>
<csml:comment type="text">Indirect</csml:comment>
</csml:comments>
</csml:connector>
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<csml:connectorSimulationProperty>
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</csml:connector>
<csml:processSimulationProperty>
<csml:priority value="0"/>
<csml:firing firingOnce="false" firingStyle="csml-firingStyle:and" type="csml-variable:Boolean" value="true"/>
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<csml:comments>
<csml:comment type="text">PMID: 17273997
Engagement of TLR-9 triggers not only the MyD88-&gt;IRF-1-&gt;IFN-beta pathway in mDC and the MyD88-&gt;IRF-7-&gt;IFN-alpha pathway in pDC, but also the MyD88-&gt;TRAF6 pathway that activates NF-kappaB in both cell types.

PMID: 17273997, 16932750
Simultaneous activation of IRF-7 by viral infection leads to IRF-7-mediated induction of IFN-alpha.</csml:comment>
</csml:comments>
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<csml:connectorFiring connectorFiringStyle="csml-connectorFiringStyle:threshold" value="0"/>
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</csml:connector>
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<csml:connectorFiring connectorFiringStyle="csml-connectorFiringStyle:threshold" value="0"/>
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<csml:connector id="c131" name="c131" refID="e68" type="cso30:c:OutputProcess">
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<csml:connectorFiring connectorFiringStyle="csml-connectorFiringStyle:threshold" value="0"/>
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<csml:comments>
<csml:comment type="text">PMID: 17273997, 16236719
Moreover, MyD88 also recruits IRF-4, which acts a negative regulator of TLR signaling.</csml:comment>
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</csml:connector>
<csml:processSimulationProperty>
<csml:priority value="0"/>
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<csml:delay delayStyle="nodelay" value="0.0"/>
<csml:processKinetic calcStyle="csml-calcStyle:speed" fast="false" kineticStyle="csml-kineticStyle:mass">
<csml:parameter key="coefficient1" value="0.1"/>
<csml:parameter key="coefficient2" value="1.0"/>
</csml:processKinetic>
</csml:processSimulationProperty>
<csml:viewProperty viewID="">
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<csml:comments>
<csml:comment type="text">PMID: 17273997
Recent studies have identified pattern recognition receptors distinct from TLR, two of which, RIG-I (retinoic acid-inducible gene-I) and MDA-5 (melanoma differentiation-associated gene 5), are cytosolic RNA helicases that detect viral RNA.</csml:comment>
</csml:comments>
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<csml:comments>
<csml:comment type="text">PMID: 17273997
Recent studies have identified pattern recognition receptors distinct from TLR, two of which, RIG-I (retinoic acid-inducible gene-I) and MDA-5 (melanoma differentiation-associated gene 5), are cytosolic RNA helicases that detect viral RNA.</csml:comment>
</csml:comments>
</csml:process>
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In all cells, the cytoplasmic sensors of dsRNA, MDA-5 and RIG-I, signal through the mitochondrial protein IPS-1 (interferon-beta promoter stimulator 1), which initiates a TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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In all cells, the cytoplasmic sensors of dsRNA, MDA-5 and RIG-I, signal through the mitochondrial protein IPS-1 (interferon-beta promoter stimulator 1), which initiates a TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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<csml:comment type="text">PMID: 17273997
In all cells, the cytoplasmic sensors of dsRNA, MDA-5 and RIG-I, signal through the mitochondrial protein IPS-1 (interferon-beta promoter stimulator 1), which initiates a TBK-&gt;IKKepsilon-&gt;IRF-3-&gt;IFN-beta pathway.</csml:comment>
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<csml:comment type="text">PMID: 17273997
Importantly, they found that IFN-gamma, despite its ability to induce high levels of IRF-1, does not trigger IRF-1 activation and nuclear translocation, resulting in suboptimal induction of IFN-beta, IL-12p35 and iNOS.</csml:comment>
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<csml:comment type="text">PMID: 17273997, 9490414
Since IRF-1 has been shown to control NK- and T-cell development through induction of IL-15 [7], it is plausible that TLR-9 signaling also potentiates IL-15 secretion and IL-15-mediated NK- and T-cell responses to pathogenic infections.</csml:comment>
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<csml:comment type="text">PMID: 17273997, 17273999
In mDC and macrophages CpG-B trigger a TLR-9-&gt;MyD88-&gt;IRF-1-&gt;IFN-beta pathway.

PMID: 17273997
In contrast, when IFN-gamma signaling occurs together with TLR-9 engagement, IRF-1 is not only induced but is also activated and migrates rapidly into the nucleus to mediate efficient induction of IFN-beta, iNOS and IL-12p35.</csml:comment>
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<csml:comment type="text">PMID: 17273997, 9490414
Since IRF-1 has been shown to control NK- and T-cell development through induction of IL-15 [7], it is plausible that TLR-9 signaling also potentiates IL-15 secretion and IL-15-mediated NK- and T-cell responses to pathogenic infections.</csml:comment>
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Since IRF-1 has been shown to control NK- and T-cell development through induction of IL-15 [7], it is plausible that TLR-9 signaling also potentiates IL-15 secretion and IL-15-mediated NK- and T-cell responses to pathogenic infections.</csml:comment>
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<csml:comment type="text">PMID: 17273997
In virus-infected fibroblasts, IFN-beta has been shown to induce an autocrine-paracrine loop that engages the type I IFN receptors and the JAK/STAT pathway leading to induction of IRF-7.</csml:comment>
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<csml:comment type="text">PMID: 17273997
In virus-infected fibroblasts, IFN-beta has been shown to induce an autocrine-paracrine loop that engages the type I IFN receptors and the JAK/STAT pathway leading to induction of IRF-7.</csml:comment>
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In virus-infected fibroblasts, IFN-beta has been shown to induce an autocrine-paracrine loop that engages the type I IFN receptors and the JAK/STAT pathway leading to induction of IRF-7.</csml:comment>
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In virus-infected fibroblasts, IFN-beta has been shown to induce an autocrine-paracrine loop that engages the type I IFN receptors and the JAK/STAT pathway leading to induction of IRF-7.</csml:comment>
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