An inhibitory effect of A20 on NF-κB activation in airway epithelium upon influenza virus infection

Onose, Akira; Hashimoto, Shigeo; Hayashi, S.; Maruoka, Shuichiro; Kumasawa, Fumio; Mizumura, Kenji; Jibiki, Itsuro; Matsumoto, Ken; Gon, Yasuhiro; Kobayashi, Tomoko; Takahashi, N.; Shibata, Yasuko; Abiko, Yoshimitsu; Shibata, Toshikatsu; Shimizu, Kazufumi; Horie, Takashi

doi:10.1016/j.ejphar.2006.03.073

Cited by 45 publications

(29 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A46 contains a TIR domain and interacts with MyD88 and several other adaptor proteins to inhibit MyD88-dependent NF-B activation through a number of TLRs (59). Finally, proteins encoded by genes in influenza virus and human cytomegalovirus (HCMV) have also been shown to inhibit NF-B activation, although the mechanism of action of these proteins remains to be determined (5,18,49,64). Thus, HSV ICP0 blocks TLR signaling at an early stage in the pathway by a unique mechanism.…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus Immediate-Early ICP0 Protein Inhibits Toll-Like Receptor 2-Dependent Inflammatory Responses and NF-κB Signaling

Lint

Murawski

Goodbody

et al. 2010

J Virol

122

114

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus Immediate-Early ICP0 Protein Inhibits Toll-Like Receptor 2-Dependent Inflammatory Responses and NF-κB Signaling

Lint

Murawski

Goodbody

et al. 2010

J Virol

122

114

View full text Add to dashboard Cite

“…Within the innate inflammatory immune response, A20 regulates NF-κB signaling at the level of TRAF6 in mouse embryonic fibroblasts and osteoclasts (17,18). In cultured human airway epithelial cells, A20 is rapidly induced by viral or bacterial compounds (21) and is essential for termination of the TLR4 signal (22). PNECs stimulated with P. aeruginosa LPS show a transient increase in A20, but CF PNECs display lower A20 expression basally and after LPS stimulation (12,23).…”

Section: Cf Airway Inflammationmentioning

confidence: 99%

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Malcomson

Wilson

Veglia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections' map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o−, CFBE41o−) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells.A20 | NF-κB | connectivity mapping | drug repositioning | CF airway inflammation

show abstract

“…A20 2/2 murine embryonic fibroblasts depict prolonged NFkB activation in response to stimulation by TNF-a, and mice null for A20 show elevated sensitivity to endotoxic shock further suggesting that A20 might negatively regulate TLR-initiated signaling pathways (12). Recently, the role of A20 has been implicated in diseases like influenza and measles, where elevated levels of this protein in the host has been shown to be correlated with the establishment of the disease (13,14).…”

mentioning

confidence: 99%

Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

Srivastav

Kar

Chande

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

TLRs, which form an interface between mammalian host and microbe, play a key role in pathogen recognition and initiation of proinflammatory response thus stimulating antimicrobial activity and host survival. However, certain intracellular pathogens such as Leishmania can successfully manipulate the TLR signaling, thus hijacking the defensive strategies of the host. Despite the presence of lipophosphoglycan, a TLR2 ligand capable of eliciting host-defensive cytokine response, on the surface of Leishmania, the strategies adopted by the parasite to silence the TLR2-mediated proinflammatory response is not understood. In this study, we showed that Leishmania donovani modulates the TLR2-mediated pathway in macrophages through inhibition of the IKK–NF-κB cascade and suppression of IL-12 and TNF-α production. This may be due to impairment of the association of TRAF6 with the TAK–TAB complex, thus inhibiting the recruitment of TRAF6 in TLR2 signaling. L. donovani infection drastically reduced Lys 63-linked ubiquitination of TRAF6, and the deubiquitinating enzyme A20 was found to be significantly upregulated in infected macrophages. Small interfering RNA-mediated silencing of A20 restored the Lys 63-linked ubiquitination of TRAF6 as well as IL-12 and TNF-α levels with a concomitant decrease in IL-10 and TGF-β synthesis in infected macrophages. Knockdown of A20 led to lower parasite survival within macrophages. Moreover, in vivo silencing of A20 by short hairpin RNA in BALB/c mice led to increased NF-κB DNA binding and host-protective proinflammatory cytokine response resulting in effective parasite clearance. These results suggest that L. donovani might exploit host A20 to inhibit the TLR2-mediated proinflammatory gene expression, thus escaping the immune responses of the host.

show abstract

An inhibitory effect of A20 on NF-κB activation in airway epithelium upon influenza virus infection

Cited by 45 publications

References 39 publications

Herpes Simplex Virus Immediate-Early ICP0 Protein Inhibits Toll-Like Receptor 2-Dependent Inflammatory Responses and NF-κB Signaling

Herpes Simplex Virus Immediate-Early ICP0 Protein Inhibits Toll-Like Receptor 2-Dependent Inflammatory Responses and NF-κB Signaling

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

Contact Info

Product

Resources

About