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NF-κB and IRF pathways: cross-regulation on target genes promoter level.

Iwanaszko M, Kimmel M - BMC Genomics (2015)

Bottom Line: The NF-κB and IRF transcription factor families are major players in inflammation and antiviral response and act as two major effectors of the innate immune response (IIR).The regulatory mechanisms of activation of these two pathways and their interactions during the IIR are only partially known.We conclude that members of the NF-κB family may directly impact regulation of IRF family, while IRF members impact regulation of NF-κB family rather indirectly, via other transcription factors such as AP-1 and SP1.

View Article: PubMed Central - PubMed

Affiliation: Systems Engineering Group, Silesian University of Technology, Gliwice, Poland. marta.iwanaszko@polsl.pl.

ABSTRACT

Background: The NF-κB and IRF transcription factor families are major players in inflammation and antiviral response and act as two major effectors of the innate immune response (IIR). The regulatory mechanisms of activation of these two pathways and their interactions during the IIR are only partially known.

Results: Our in silico findings report that there is cross-regulation between both pathways at the level of gene transcription regulation, mediated by the presence of binding sites for both factors in promoters of genes essential for these pathways. These findings agree with recent experimental data reporting crosstalk between pathways activated by RIG-I and TLR3 receptors in response to pathogens.

Conclusions: We present an extended crosstalk diagram of the IRF - NF-κB pathways. We conclude that members of the NF-κB family may directly impact regulation of IRF family, while IRF members impact regulation of NF-κB family rather indirectly, via other transcription factors such as AP-1 and SP1.

No MeSH data available.


Related in: MedlinePlus

Cross-signaling schematic. Signaling pathways activated by viral by-products and involving potential targets for IRF3, NF-κB and SP1 (including their main target, IFNβ). Green arrows: confirmed positive regulation. Red lines with bullet endings: confirmed negative regulation. Blue dashed arrows: Co-regulation of unknown type inferred from bioinformatics and evolutionary analysis. Bold lines: Strong association of TF based on high counts of binding sites in target gene promoters.
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Fig1: Cross-signaling schematic. Signaling pathways activated by viral by-products and involving potential targets for IRF3, NF-κB and SP1 (including their main target, IFNβ). Green arrows: confirmed positive regulation. Red lines with bullet endings: confirmed negative regulation. Blue dashed arrows: Co-regulation of unknown type inferred from bioinformatics and evolutionary analysis. Bold lines: Strong association of TF based on high counts of binding sites in target gene promoters.

Mentions: Our cross-regulation hypothesis, based on in silico methods is supported by experimental results. Gene knockdown experiments [13] show that levels of RelA are increased by IRF3 siRNA silencing, suggesting that IRF3 may be a negative regulator of RelA expression. In addition, silencing RelA resulted in upregulation of the IRF3 expression levels. Similar results were observed for known NF-κB-dependent genes, such as IL6 or IKBA, expression levels of which were upregulated in response to IRF3 silencing. We show these interactions in Figure 1, which is a proposed conceptual diagram describing interactions between NF-κB and IRF3 pathways at gene promoter level. Presence of interactions between respective transcription factors is based on in silico TFBS data with CHIP-seq support as discussed earlier on in the paper, while direction of this interaction is based on literature (green lines) or concluded from experimental data (red lines) [13]. Crosstalk between the two arms of the IIR system, at the level of interactions between genes coding for NF-κB and IRF3 transcription factors and these transcription factors, was not presented before. The results are also consistent with the findings of Wang et al. [27], who show that overexpression of IRF3 in hepatocytes results in IKKβ/NF-κB signaling downregulation [27].Figure 1


NF-κB and IRF pathways: cross-regulation on target genes promoter level.

Iwanaszko M, Kimmel M - BMC Genomics (2015)

Cross-signaling schematic. Signaling pathways activated by viral by-products and involving potential targets for IRF3, NF-κB and SP1 (including their main target, IFNβ). Green arrows: confirmed positive regulation. Red lines with bullet endings: confirmed negative regulation. Blue dashed arrows: Co-regulation of unknown type inferred from bioinformatics and evolutionary analysis. Bold lines: Strong association of TF based on high counts of binding sites in target gene promoters.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4430024&req=5

Fig1: Cross-signaling schematic. Signaling pathways activated by viral by-products and involving potential targets for IRF3, NF-κB and SP1 (including their main target, IFNβ). Green arrows: confirmed positive regulation. Red lines with bullet endings: confirmed negative regulation. Blue dashed arrows: Co-regulation of unknown type inferred from bioinformatics and evolutionary analysis. Bold lines: Strong association of TF based on high counts of binding sites in target gene promoters.
Mentions: Our cross-regulation hypothesis, based on in silico methods is supported by experimental results. Gene knockdown experiments [13] show that levels of RelA are increased by IRF3 siRNA silencing, suggesting that IRF3 may be a negative regulator of RelA expression. In addition, silencing RelA resulted in upregulation of the IRF3 expression levels. Similar results were observed for known NF-κB-dependent genes, such as IL6 or IKBA, expression levels of which were upregulated in response to IRF3 silencing. We show these interactions in Figure 1, which is a proposed conceptual diagram describing interactions between NF-κB and IRF3 pathways at gene promoter level. Presence of interactions between respective transcription factors is based on in silico TFBS data with CHIP-seq support as discussed earlier on in the paper, while direction of this interaction is based on literature (green lines) or concluded from experimental data (red lines) [13]. Crosstalk between the two arms of the IIR system, at the level of interactions between genes coding for NF-κB and IRF3 transcription factors and these transcription factors, was not presented before. The results are also consistent with the findings of Wang et al. [27], who show that overexpression of IRF3 in hepatocytes results in IKKβ/NF-κB signaling downregulation [27].Figure 1

Bottom Line: The NF-κB and IRF transcription factor families are major players in inflammation and antiviral response and act as two major effectors of the innate immune response (IIR).The regulatory mechanisms of activation of these two pathways and their interactions during the IIR are only partially known.We conclude that members of the NF-κB family may directly impact regulation of IRF family, while IRF members impact regulation of NF-κB family rather indirectly, via other transcription factors such as AP-1 and SP1.

View Article: PubMed Central - PubMed

Affiliation: Systems Engineering Group, Silesian University of Technology, Gliwice, Poland. marta.iwanaszko@polsl.pl.

ABSTRACT

Background: The NF-κB and IRF transcription factor families are major players in inflammation and antiviral response and act as two major effectors of the innate immune response (IIR). The regulatory mechanisms of activation of these two pathways and their interactions during the IIR are only partially known.

Results: Our in silico findings report that there is cross-regulation between both pathways at the level of gene transcription regulation, mediated by the presence of binding sites for both factors in promoters of genes essential for these pathways. These findings agree with recent experimental data reporting crosstalk between pathways activated by RIG-I and TLR3 receptors in response to pathogens.

Conclusions: We present an extended crosstalk diagram of the IRF - NF-κB pathways. We conclude that members of the NF-κB family may directly impact regulation of IRF family, while IRF members impact regulation of NF-κB family rather indirectly, via other transcription factors such as AP-1 and SP1.

No MeSH data available.


Related in: MedlinePlus