An explanation was presented by Covert et al. In the canonical model, IFN regulation, after RNA virus infection, is conducted by IRF-3 and IRF-7. Single-cell imaging experiments have provided information about cellular heterogeneity of these interactions but exact molecular mechanisms are not clear yet. Recent work by the Brasier’s group and others has shown that IRF3-dependent and NF-κB-dependent pathways are interconnected at multiple steps, with the final shared component being the IκB kinase-γ (IKKγ) subunit. The regulatory mechanisms of activation of these two pathways and their interactions during the IIR are only partially known. In this paper we analyze crosstalk between the two major signaling pathways in the IIR system, namely the NF-κB and IRF pathways.
#NFKB PROMOTEE ACTIVATOR#
Stimulation of TLRs (Toll-Like Receptors) by a pathogen induces activation of signal transduction cascades, which leads to translocation of nuclear factor-κB (NF-κB) to the nucleus, activation of interferon regulatory factors 3/7 (IRF3/7) and/or activator protein-1 (AP-1), which cooperate to induce transcription of various cytokines such as alpha/beta interferon (IFN-α/β) to counteract infection. Identification of pathogen-associated molecules, such as dsRNA and lipopolysaccharide (LPS), by host pattern recognition receptors (PRRs) is a critical step in innate immune response (IIR). 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. We present an extended crosstalk diagram of the IRF - NF-κB pathways. These findings agree with recent experimental data reporting crosstalk between pathways activated by RIG-I and TLR3 receptors in response to pathogens. 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.
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).
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