Essential role of IRF-3 in lipopolysaccharide-induced interferon-β gene expression and endotoxin shock

Sakaguchi, Shoji; Negishi, Hideo; Asagiri, Masataka; Nakajima, Chihiro; Mizutani, Tatsumi; Takaoka, Akinori; Honda, Kenya; Taniguchi, Tadatsugu

doi:10.1016/s0006-291x(03)01049-0

Cited by 241 publications

(212 citation statements)

References 38 publications

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“…5D). As negative control, we also measured the expression of IRF-3, a member of the same family of IFN regulatory factors that is involved in the signaling pathway downstream of TLRs and is not induced by type I IFNs (39). We confirmed that IRF-3 was not up-regulated by IFN-␣ and found that IL-4 did not affect its expression (Fig.…”

Section: Il-4 Suppresses the Expression Of Ifn-responsive Genes In Bmmentioning

confidence: 54%

IL-4 Suppresses Dendritic Cell Response to Type I Interferons

Sriram

Biswas

Behrens

et al. 2007

The Journal of Immunology

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Cytokines play an important role in modulating the development and function of dendritic cells (DCs). Type I IFNs activate DCs and drive anti-viral responses, whereas IL-4 is the prototype of a Th2 cytokine. Evidence suggests that type I IFNs and IL-4 influence each other to modulate DC functions. We found that two type I IFNs, IFN-α and IFN-β, stimulated a similar costimulatory profile in myeloid resting DCs. IL-4 suppressed the response of myeloid DCs to both type I IFNs in vitro and in vivo by impairing the up-regulation of MHC and costimulatory molecules and the production of cytokines, such as IL-6 and IL-15, and anti-viral genes, such as Mx-1, upon type I IFN stimulation. In dissecting the mechanism underlying this inhibition, we characterized the positive feedback loop that is triggered by IFN-α in primary DCs and found that IL-4 inhibited the initial phosphorylation of STAT1 and STAT2 (the transducers of signaling downstream of IFN-α and -β receptors (IFNARs)) and reduced the up-regulation of genes involved in the amplification of the IFN response such as IRF-7, STAT1, STAT2, IFN-β, and the IFNARs in vitro and in vivo. Therefore, IL-4 renders myeloid DCs less responsive to paracrine type I IFNs and less potent in sustaining the autocrine positive loop that normally amplifies the effects of type I IFNs. This inhibition could explain the increased susceptibility to viral infections observed during Th2-inducing parasitoses.

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Section: Il-4 Suppresses the Expression Of Ifn-responsive Genes In Bmmentioning

confidence: 54%

IL-4 Suppresses Dendritic Cell Response to Type I Interferons

Sriram

Biswas

Behrens

et al. 2007

The Journal of Immunology

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“…In addition, recent reports showing that mice deficient in suppressor of cytokine signaling-1, IL-1R-associated kinase M, or ST2, a negative regulator of NF-B signaling, are hypersensitive to endotoxin shock, strongly suggest that negative feedback regulation of TLR signaling is important to protect the host from excessive immune response (25)(26)(27)(28). Because IRF-3 is known to mediate endotoxin shock or virus-induced cell death, the IRF-3 activity should also be strictly controlled (29,30). Several negative regulators of TLRtriggered NF-B signaling were identified, but those of IRF-3 signaling have not been described except for IRF-2, which competes with IRF-3 for the recruitment of CREB binding protein (31).…”

Section: Discussionmentioning

confidence: 99%

A20 Is a Negative Regulator of IFN Regulatory Factor 3 Signaling

Saitoh

Yamamoto

Miyagishi

et al. 2005

The Journal of Immunology

169

137

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IFN regulatory factor 3 (IRF-3) is a critical transcription factor that regulates an establishment of innate immune status following detection of viral pathogens. Recent studies have revealed that two IκB kinase (IKK)-like kinases, NF-κB-activating kinase/Traf family member-associated NF-κB activator-binding kinase 1 and IKK-i/IKKε, are responsible for activation of IRF-3, but the regulatory mechanism of the IRF-3 signaling pathway has not been fully understood. In this study, we report that IRF-3 activation is suppressed by A20, which was initially identified as an inhibitor of apoptosis and inducibly expressed by dsRNA. A20 physically interacts with NF-κB-activating kinase/Traf family member-associated NF-κB activator-binding kinase 1 and IKK-i/IKKε, and inhibits dimerization of IRF-3 following engagement of TLR3 by dsRNA or Newcastle disease virus infection, leading to suppression of the IFN stimulation response element- and IFN-β promoter-dependent transcription. Importantly, knocking down of A20 expression by RNA interference results in enhanced IRF-3-dependent transcription triggered by the stimulation of TLR3 or virus infection. Our study thus demonstrates that A20 is a candidate negative regulator of the signaling cascade to IRF-3 activation in the innate antiviral response.

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“…In addition, STAT1-null mice are also resistant to LPS (30). Furthermore, IRF-3 Ϫ/Ϫ mice are resistant to LPS and show defects in the induction of IFN-␤ and chemokine (C-X-C motif) ligand 10 (CXCL10) mRNA (36). SPRET͞Ei seems to be unique in that the defect is specific to IFN-␤ induction, because other IRF-3-responsive genes, such as Cxcl10 and Isg15, are induced with comparable kinetics in SPRET͞Ei and C57BL͞6, and phosphorylation of IRF-3 ap- pears normal in SPRET͞Ei macrophages.…”

Section: Discussionmentioning

confidence: 99%