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Indirect


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PMID: 16979939
Currently, Toll-like receptor (TLR)9 is the only known receptor to detect immunostimulatory DNA such as CpG DNA.

PMID: 16979939, 16467569, 12119352, 16670302
It is of note that a phosphoinositide 3-kinase (PI 3-kinase), possibly class III vacuolar protein sorting 34 (VPS34), which is required for endosome fusion and membrane trafficking [33], has been shown to play a crucial role in internalization of CpG ODNs as well as TLR9-mediated immune activation.

PMID: 16979939, 12960360
By contrast, Fcgamma receptor IIa inhibits TLR9-mediated activation if DNA does not form a complex with IgG.</csml:comment>
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PMID: 16979939, 15630134
Moreover, a heme polymer, so-called hemozoin, generated as a heme metabolite during malarial infection of red blood cells, was found to be a unique non-DNA TLR9 ligand.</csml:comment>
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PMID: 16979939, 15197227, 15668740, 16849465
Supporting this notion, these processes can be further enhanced either by coupling microbial or host DNA with anti-DNA antibody [through Fcgamma receptor IIa (human) and III (mouse)] [42 and 43], or by encapsulation with cationic liposomes [44], or by a certain scavenger receptor (such as CXCL16 [45]).</csml:comment>
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PMID: 16979939, 15197227, 15668740, 16849465
Supporting this notion, these processes can be further enhanced either by coupling microbial or host DNA with anti-DNA antibody [through Fcgamma receptor IIa (human) and III (mouse)] [42 and 43], or by encapsulation with cationic liposomes [44], or by a certain scavenger receptor (such as CXCL16 [45]).</csml:comment>
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PMID: 16979939, 15197227, 15668740, 16849465
Supporting this notion, these processes can be further enhanced either by coupling microbial or host DNA with anti-DNA antibody [through Fcgamma receptor IIa (human) and III (mouse)] [42 and 43], or by encapsulation with cationic liposomes [44], or by a certain scavenger receptor (such as CXCL16 [45]).</csml:comment>
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PMID: 16979939, 16365150,  16148144, 14993594
urthermore, TLR9 was found to cooperate with TLR2 to combat intracellular bacteria such as Mycobacterium tuberculosis [46] and Brucella abortus [47], and with TLR3 against mouse cytomegaloviru.</csml:comment>
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PMID: 16979939, 16365150,  16148144, 14993594
urthermore, TLR9 was found to cooperate with TLR2 to combat intracellular bacteria such as Mycobacterium tuberculosis [46] and Brucella abortus [47], and with TLR3 against mouse cytomegaloviru.</csml:comment>
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PMID: 16979939, 16365150,  16148144, 14993594
urthermore, TLR9 was found to cooperate with TLR2 to combat intracellular bacteria such as Mycobacterium tuberculosis [46] and Brucella abortus [47], and with TLR3 against mouse cytomegaloviru.</csml:comment>
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PMID: 16979939, 16365150,  16148144, 14993594
urthermore, TLR9 was found to cooperate with TLR2 to combat intracellular bacteria such as Mycobacterium tuberculosis [46] and Brucella abortus [47], and with TLR3 against mouse cytomegaloviru.</csml:comment>
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PMID: 16979939, 12960360
By contrast, Fcgamma receptor IIa inhibits TLR9-mediated activation if DNA does not form a complex with IgG.</csml:comment>
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</csml:comment>
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<csml:comment type="text">
PMID: 16979939, 16791898, 16301648, 15661046
Moreover, growing recent evidence indicates that TLR9 expression and/or function can be upregulated in B cells [53] and other cell types, such as macrophages or cDCs stimulated with IFNbeta [52] or IFNgamma [54 and 55], monocytes infected with Yersinia pestis [56], granulocytes stimulated with granulocyte&#8211;macrophage colony-stimulating factor [57 and 58], and even epithelial cells cultured with transforming growth factor (TGFalpha).

PMID: 16979939, 16827891
Very recently, Shirota et al. showed that dsDNA-induced IFNbeta was necessary for the production of chemokines and nitric oxide by stimulated macrophages.</csml:comment>
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PMID: 16979939, 16791898, 16301648, 15661046
Moreover, growing recent evidence indicates that TLR9 expression and/or function can be upregulated in B cells [53] and other cell types, such as macrophages or cDCs stimulated with IFNbeta [52] or IFNgamma [54 and 55], monocytes infected with Yersinia pestis [56], granulocytes stimulated with granulocyte&#8211;macrophage colony-stimulating factor [57 and 58], and even epithelial cells cultured with transforming growth factor (TGFalpha).</csml:comment>
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Indirect</csml:comment>
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PMID: 16979939, 16791898, 16301648, 15661046
Moreover, growing recent evidence indicates that TLR9 expression and/or function can be upregulated in B cells [53] and other cell types, such as macrophages or cDCs stimulated with IFNbeta [52] or IFNgamma [54 and 55], monocytes infected with Yersinia pestis [56], granulocytes stimulated with granulocyte&#8211;macrophage colony-stimulating factor [57 and 58], and even epithelial cells cultured with transforming growth factor (TGFalpha).</csml:comment>
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Indirect</csml:comment>
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PMID: 16979939, 16791898, 16301648, 15661046
Moreover, growing recent evidence indicates that TLR9 expression and/or function can be upregulated in B cells [53] and other cell types, such as macrophages or cDCs stimulated with IFNbeta [52] or IFNgamma [54 and 55], monocytes infected with Yersinia pestis [56], granulocytes stimulated with granulocyte&#8211;macrophage colony-stimulating factor [57 and 58], and even epithelial cells cultured with transforming growth factor (TGFalpha).</csml:comment>
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<csml:comment type="text">


PMID: 16979939, 16791898, 16301648, 15661046
Moreover, growing recent evidence indicates that TLR9 expression and/or function can be upregulated in B cells [53] and other cell types, such as macrophages or cDCs stimulated with IFNbeta [52] or IFNgamma [54 and 55], monocytes infected with Yersinia pestis [56], granulocytes stimulated with granulocyte&#8211;macrophage colony-stimulating factor [57 and 58], and even epithelial cells cultured with transforming growth factor (TGFalpha).</csml:comment>
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Indirect</csml:comment>
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<csml:comment type="text">


PMID: 16979939, 16791898, 16301648, 15661046
Moreover, growing recent evidence indicates that TLR9 expression and/or function can be upregulated in B cells [53] and other cell types, such as macrophages or cDCs stimulated with IFNbeta [52] or IFNgamma [54 and 55], monocytes infected with Yersinia pestis [56], granulocytes stimulated with granulocyte&#8211;macrophage colony-stimulating factor [57 and 58], and even epithelial cells cultured with transforming growth factor (TGFalpha).</csml:comment>
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Indirect</csml:comment>
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PMID: 16979939, 16791898, 16301648, 15661046
Moreover, growing recent evidence indicates that TLR9 expression and/or function can be upregulated in B cells [53] and other cell types, such as macrophages or cDCs stimulated with IFNbeta [52] or IFNgamma [54 and 55], monocytes infected with Yersinia pestis [56], granulocytes stimulated with granulocyte&#8211;macrophage colony-stimulating factor [57 and 58], and even epithelial cells cultured with transforming growth factor (TGFalpha).</csml:comment>
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PMID: 16979939, 16791898, 16301648, 15661046
Moreover, growing recent evidence indicates that TLR9 expression and/or function can be upregulated in B cells [53] and other cell types, such as macrophages or cDCs stimulated with IFNbeta [52] or IFNgamma [54 and 55], monocytes infected with Yersinia pestis [56], granulocytes stimulated with granulocyte&#8211;macrophage colony-stimulating factor [57 and 58], and even epithelial cells cultured with transforming growth factor (TGFalpha).</csml:comment>
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PMID: 16979939, 16497588
Following TLR9 stimulation, MyD88 subsequently associates with IL-1R-associated kinase 4 (IRAK4), IFN regulatory factor (IRF5) and tumor necrosis factor receptor-associated factor 6 (TRAF6), culminating in the activation of nuclear factor (NF)-kappaB and/or the mitogen-activated protein (MAP) kinase pathway, resulting in the production of pro-inflammatory molecules including cytokines and chemokines.</csml:comment>
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PMID: 16979939, 16497588
Following TLR9 stimulation, MyD88 subsequently associates with IL-1R-associated kinase 4 (IRAK4), IFN regulatory factor (IRF5) and tumor necrosis factor receptor-associated factor 6 (TRAF6), culminating in the activation of nuclear factor (NF)-kappaB and/or the mitogen-activated protein (MAP) kinase pathway, resulting in the production of pro-inflammatory molecules including cytokines and chemokines.</csml:comment>
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PMID: 16979939, 16186825, 16862162
TRAF6 forms a complex with ubiquitin-conjugating (Ubc) enzymes such as Ubc13, and activates TGFbeta-activated kinase 1 (TAK1), and both Ubc13 and TAK1 are necessary for TLR9-mediated activation of NF-kappaB and activator protein-1 (AP-1) through the canonical IkappaB kinase (IKK) complex and MAP kinase.</csml:comment>
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PMID: 16979939, 16186825, 16862162
TRAF6 forms a complex with ubiquitin-conjugating (Ubc) enzymes such as Ubc13, and activates TGFbeta-activated kinase 1 (TAK1), and both Ubc13 and TAK1 are necessary for TLR9-mediated activation of NF-kappaB and activator protein-1 (AP-1) through the canonical IkappaB kinase (IKK) complex and MAP kinase.</csml:comment>
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Indirect</csml:comment>
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PMID: 16979939, 16186825, 16862162
TRAF6 forms a complex with ubiquitin-conjugating (Ubc) enzymes such as Ubc13, and activates TGFbeta-activated kinase 1 (TAK1), and both Ubc13 and TAK1 are necessary for TLR9-mediated activation of NF-kappaB and activator protein-1 (AP-1) through the canonical IkappaB kinase (IKK) complex and MAP kinase.</csml:comment>
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Indirect</csml:comment>
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PMID: 16979939, 16186825, 16862162
TRAF6 forms a complex with ubiquitin-conjugating (Ubc) enzymes such as Ubc13, and activates TGFbeta-activated kinase 1 (TAK1), and both Ubc13 and TAK1 are necessary for TLR9-mediated activation of NF-kappaB and activator protein-1 (AP-1) through the canonical IkappaB kinase (IKK) complex and MAP kinase.</csml:comment>
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PMID: 16979939, 16186825, 16862162
TRAF6 forms a complex with ubiquitin-conjugating (Ubc) enzymes such as Ubc13, and activates TGFbeta-activated kinase 1 (TAK1), and both Ubc13 and TAK1 are necessary for TLR9-mediated activation of NF-kappaB and activator protein-1 (AP-1) through the canonical IkappaB kinase (IKK) complex and MAP kinase.</csml:comment>
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PMID: 16979939, 16186825, 16862162
TRAF6 forms a complex with ubiquitin-conjugating (Ubc) enzymes such as Ubc13, and activates TGFbeta-activated kinase 1 (TAK1), and both Ubc13 and TAK1 are necessary for TLR9-mediated activation of NF-kappaB and activator protein-1 (AP-1) through the canonical IkappaB kinase (IKK) complex and MAP kinase.</csml:comment>
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PMID: 16979939, 16186825, 16862162
TRAF6 forms a complex with ubiquitin-conjugating (Ubc) enzymes such as Ubc13, and activates TGFbeta-activated kinase 1 (TAK1), and both Ubc13 and TAK1 are necessary for TLR9-mediated activation of NF-kappaB and activator protein-1 (AP-1) through the canonical IkappaB kinase (IKK) complex and MAP kinase.</csml:comment>
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PMID: 16979939
In pDCs, additional molecules such as IRF7, IRAK1, TRAF3, IKK alpha and osteopontin (Opn-i) are recruited to the MyD88-containing complex, leading to robust production of type I IFNs.

PMID: 16979939, 16424890
In addition to the NF-kappaB-dependent signaling pathways controlled by these IKK complexes, TLR9 stimulation of pDCs by D/A-type CpG DNA activates another signaling pathway, resulting in type I IFN (IFNalpha and IFNbeta) production.</csml:comment>
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PMID: 16979939
IRF7 is phosphorylated by IRAK1 and translocates to the nucleus.</csml:comment>
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PMID: 16979939
IRF7 is phosphorylated by IRAK1 and translocates to the nucleus.</csml:comment>
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Indirect</csml:comment>
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Indirect</csml:comment>
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<csml:comment type="text">


PMID: 16979939
In pDCs, additional molecules such as IRF7, IRAK1, TRAF3, IKK alpha and osteopontin (Opn-i) are recruited to the MyD88-containing complex, leading to robust production of type I IFNs.

PMID: 16979939, 16424890
In addition to the NF-kappaB-dependent signaling pathways controlled by these IKK complexes, TLR9 stimulation of pDCs by D/A-type CpG DNA activates another signaling pathway, resulting in type I IFN (IFNalpha and IFNbeta) production.

PMID: 16979939, 16306936, 16306937, 16612387
Furthermore, TRAF3, IKKalpha and osteopontin, all of which are able to associate with MyD88, have recently been reported to be non-redundant for TLR9-mediated pDC production of IFNalpha [79, 80 and 81], suggesting that a large and unique signaling complex in pDCs plays an important role in robust TLR9-mediated IFNalpha production.</csml:comment>
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Indirect</csml:comment>
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<csml:comment type="text">


PMID: 16979939
In pDCs, additional molecules such as IRF7, IRAK1, TRAF3, IKK alpha and osteopontin (Opn-i) are recruited to the MyD88-containing complex, leading to robust production of type I IFNs.

PMID: 16979939, 16424890
In addition to the NF-kappaB-dependent signaling pathways controlled by these IKK complexes, TLR9 stimulation of pDCs by D/A-type CpG DNA activates another signaling pathway, resulting in type I IFN (IFNalpha and IFNbeta) production.

PMID: 16979939, 16413926
As expected, IRF3 was a necessary transcription factor for dsDNA-induced IFNbeta.

PMID: 16979939, 16715101
CpG ODNs activate cDCs to secrete IL-15 to upregulate CD40 expression, whereas CpG-activated pDCs further enhance cDC production of IL-12 through CD40 interaction with its ligand CD40L.</csml:comment>
</csml:comments>
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PMID: 16979939, 16286919, 16625202
Moreover, RIG-I and Mda-5, recently described intracellular receptors for RNA virus and/or dsRNA [82], were not required for B-DNA recognition.</csml:comment>
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PMID: 16979939, 16286919, 16625202
Moreover, RIG-I and Mda-5, recently described intracellular receptors for RNA virus and/or dsRNA [82], were not required for B-DNA recognition.</csml:comment>
</csml:comments>
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Indirect</csml:comment>
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PMID: 16979939
By contrast, dsRNA-induced type I IFN production is mediated by TBK1 and partially by IKKi, a second non-canonical IKK family member.</csml:comment>
</csml:comments>
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Indirect</csml:comment>
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<csml:comment type="text">

PMID: 16979939
By contrast, dsRNA-induced type I IFN production is mediated by TBK1 and partially by IKKi, a second non-canonical IKK family member.</csml:comment>
</csml:comments>
</csml:process>
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Indirect</csml:comment>
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PMID: 16979939
By contrast, dsRNA-induced type I IFN production is mediated by TBK1 and partially by IKKi, a second non-canonical IKK family member.

PMID: 16979939
Further studies are required to identify adaptor molecules and receptor molecules that mediate B-DNA-induced type I IFN production.</csml:comment>
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PMID: 16979939, 16286919
Nevertheless, B-DNA activates IRF3 and the IFNbeta promoter through a TBK1/IKKi-dependent pathway, whereas substantial NF-kappaB activation was observed independently of TBK1/IKKi.</csml:comment>
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PMID: 16979939, 16286919
Nevertheless, B-DNA activates IRF3 and the IFNbeta promoter through a TBK1/IKKi-dependent pathway, whereas substantial NF-kappaB activation was observed independently of TBK1/IKKi.</csml:comment>
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PMID: 16979939, 16286919
Nevertheless, B-DNA activates IRF3 and the IFNbeta promoter through a TBK1/IKKi-dependent pathway, whereas substantial NF-kappaB activation was observed independently of TBK1/IKKi.

PMID: 16979939, 16413926
As expected, IRF3 was a necessary transcription factor for dsDNA-induced IFNbeta.</csml:comment>
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PMID: 16979939, 16286919
Nevertheless, B-DNA activates IRF3 and the IFNbeta promoter through a TBK1/IKKi-dependent pathway, whereas substantial NF-kappaB activation was observed independently of TBK1/IKKi.</csml:comment>
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PMID: 16979939
This results in the robust production of type I IFNs and chemokines, and the upregulation of MHC and co-stimulatory molecules.</csml:comment>
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PMID: 16979939
This results in the robust production of type I IFNs and chemokines, and the upregulation of MHC and co-stimulatory molecules.</csml:comment>
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PMID: 16979939
This results in the robust production of type I IFNs and chemokines, and the upregulation of MHC and co-stimulatory molecules.</csml:comment>
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PMID: 16979939, 15879108, 
Yasuda et al. demonstrated that transfection with mammalian or bacterial dsDNA, but not ssODNs, using the transfection reagent DOTAP (which is known to retain DNA in the endosomes), activates macrophages and DCs to upregulate co-stimulatory markers and produce substantial amounts of TNFalpha or IL-6 in a TLR9-independent manner.</csml:comment>
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PMID: 16979939, 15879108, 
Yasuda et al. demonstrated that transfection with mammalian or bacterial dsDNA, but not ssODNs, using the transfection reagent DOTAP (which is known to retain DNA in the endosomes), activates macrophages and DCs to upregulate co-stimulatory markers and produce substantial amounts of TNFalpha or IL-6 in a TLR9-independent manner.</csml:comment>
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PMID: 16979939, 16827891
Very recently, Shirota et al. showed that dsDNA-induced IFNbeta was necessary for the production of chemokines and nitric oxide by stimulated macrophages.</csml:comment>
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PMID: 16979939, 16827891
Very recently, Shirota et al. showed that dsDNA-induced IFNbeta was necessary for the production of chemokines and nitric oxide by stimulated macrophages.</csml:comment>
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PMID: 16979939, 16413926
As expected, IRF3 was a necessary transcription factor for dsDNA-induced IFNbeta.</csml:comment>
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PMID: 16979939, 16424890, 16286919
IPS-1 (also known as MAVS, Cardif or VISA), an essential adaptor molecule for RIG-I- and Mda-5-mediated RNA recognition [78], was shown to be involved in B-DNA-transfected 293 cell activation of IFNbeta and the ELAM-1 (NF-kappaB) promoter.</csml:comment>
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PMID: 16979939, 16424890, 16286919
IPS-1 (also known as MAVS, Cardif or VISA), an essential adaptor molecule for RIG-I- and Mda-5-mediated RNA recognition [78], was shown to be involved in B-DNA-transfected 293 cell activation of IFNbeta and the ELAM-1 (NF-kappaB) promoter.</csml:comment>
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PMID: 16979939, 16424890, 16286919
IPS-1 (also known as MAVS, Cardif or VISA), an essential adaptor molecule for RIG-I- and Mda-5-mediated RNA recognition [78], was shown to be involved in B-DNA-transfected 293 cell activation of IFNbeta and the ELAM-1 (NF-kappaB) promoter.</csml:comment>
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PMID: 16979939, 16424890, 16286919
IPS-1 (also known as MAVS, Cardif or VISA), an essential adaptor molecule for RIG-I- and Mda-5-mediated RNA recognition [78], was shown to be involved in B-DNA-transfected 293 cell activation of IFNbeta and the ELAM-1 (NF-kappaB) promoter.</csml:comment>
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PMID: 16979939, 16424890, 16286919
IPS-1 (also known as MAVS, Cardif or VISA), an essential adaptor molecule for RIG-I- and Mda-5-mediated RNA recognition [78], was shown to be involved in B-DNA-transfected 293 cell activation of IFNbeta and the ELAM-1 (NF-kappaB) promoter.</csml:comment>
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PMID: 16979939, 16424890, 16286919
IPS-1 (also known as MAVS, Cardif or VISA), an essential adaptor molecule for RIG-I- and Mda-5-mediated RNA recognition [78], was shown to be involved in B-DNA-transfected 293 cell activation of IFNbeta and the ELAM-1 (NF-kappaB) promoter.</csml:comment>
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PMID: 16979939, 15057783, 16763660
In the best-characterized animal model, in which CpG ODNs trigger a TLR9-mediated protective innate immune response to various infectious agents such as Listeria monocytogenes 3 and 5, for example, the protection requires DC production of IL-12, IFNgamma and IL-15, but not IL-18 or type I IFNs.</csml:comment>
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PMID: 16979939, 15057783, 16763660
In the best-characterized animal model, in which CpG ODNs trigger a TLR9-mediated protective innate immune response to various infectious agents such as Listeria monocytogenes 3 and 5, for example, the protection requires DC production of IL-12, IFNgamma and IL-15, but not IL-18 or type I IFNs.</csml:comment>
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PMID: 16979939, 15057783, 16763660
In the best-characterized animal model, in which CpG ODNs trigger a TLR9-mediated protective innate immune response to various infectious agents such as Listeria monocytogenes 3 and 5, for example, the protection requires DC production of IL-12, IFNgamma and IL-15, but not IL-18 or type I IFNs.

PMID: 16979939, 16715101
CpG ODNs activate cDCs to secrete IL-15 to upregulate CD40 expression, whereas CpG-activated pDCs further enhance cDC production of IL-12 through CD40 interaction with its ligand CD40L.</csml:comment>
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PMID: 16979939, 16715101
CpG ODNs activate cDCs to secrete IL-15 to upregulate CD40 expression, whereas CpG-activated pDCs further enhance cDC production of IL-12 through CD40 interaction with its ligand CD40L.</csml:comment>
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PMID: 16979939, 16715101
CpG ODNs activate cDCs to secrete IL-15 to upregulate CD40 expression, whereas CpG-activated pDCs further enhance cDC production of IL-12 through CD40 interaction with its ligand CD40L.</csml:comment>
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PMID: 16979939, 16715101
CpG ODNs activate cDCs to secrete IL-15 to upregulate CD40 expression, whereas CpG-activated pDCs further enhance cDC production of IL-12 through CD40 interaction with its ligand CD40L.</csml:comment>
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