Regulation of Toll-like receptor 4 signalling by A20 zinc finger protein.
A20 is a zinc finger protein that renders cells resistant to apoptosis. However, the recent demonstration that A20-deficient mice develop severe inflammation and are hyper-responsive to LPS suggests that A20 may play a key role in regulating the inflammatory response. This study, for the first time, explores the likely mechanism by which A20 can regulate the pro-inflammatory effects of LPS. More specifically it characterises the ability of A20 to modulate TLR-4 signalling since TLR-4 acts as the signalling receptor system for LPS. Full length A20 inhibited the ability of TLR-4 to activate the transcription factors, NF-kappa B and AP-1, and induce the chemokine IL-8. The inhibitory capacity of A20 on NF-kappa B was localised to the C-terminal zinc finger domain of A20 whereas full length A20 was required to effect inhibition of AP-1 and IL-8. Furthermore full length and C-terminal A20 showed similar regulatory effects on MEKK-1 activation of NF-kappa B and AP-1 and induction of IL-8. The findings increase our mechanistic understanding of the anti-inflammatory effects of A20 and suggest that it modulates TLR-4 signalling at or downstream of MEKK-1.
O'Reilly
Susan M
SM
Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Moynagh
Paul N
PN
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins; D004926:Escherichia coli / Q000235:genetics; D017930:Genes, Reporter; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D048728:MAP Kinase Kinase Kinase 1; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse