TNF-alpha-induced tolerance to ischemic injury involves differential control of NF-kappaB transactivation: the role of NF-kappaB association with p300 adaptor.
Preconditioning with sublethal ischemia results in natural tolerance to ischemic stress, where multiple mediators of ischemic damage are simultaneously counteracted. Tumor necrosis factor alpha (TNF-alpha) has been implicated in development of ischemic tolerance. Using cellular models of ischemic tolerance, we have demonstrated that an effector of TNF-alpha-induced preconditioning is ceramide, a sphingolipid messenger in TNF-alpha signaling. TNF-alpha/ceramide-induced preconditioning protected cultured neurons against ischemic death and cultured astrocytes against proinflammatory effects of TNF-alpha. TNF-alpha activates a transcription factor NF-kappaB that binds promoters of multiple genes, thus ensuring pleiotropic effects of TNF-alpha. We describe here a mechanism that allows selective suppression of TNF-alpha/NF-kappaB-induced harmful genes in preconditioned cells while preserving cytoprotective responses. We demonstrate that in astrocytes activation of an adhesion molecule ICAM-1 by TNF-alpha is regulated through association of the phosphorylated p65 subunit of NF-kappaB with an adapter protein, p300, and that in preconditioned cells p65 remains unphosphorylated and ICAM-1 transcription is inhibited. However, TNF-alpha-activated transcription of a protective enzyme, MnSOD, does not depend on p300 and does not become inhibited in preconditioned cells. This new understanding of TNF-alpha-induced adaptation to ischemic stress and inflammation could suggest novel avenues for clinical intervention during ischemic and inflammatory diseases.
Ginis
Irene
I
Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-4092, USA.
Jaiswal
Rama
R
Klimanis
Dace
D
Liu
Jie
J
Greenspon
Jose
J
Hallenbeck
John M
JM
D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D002135:Calcium-Binding Proteins; D002518:Ceramides / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018913:Event-Related Potentials, P300 / Q000502:physiology; D019194:Ischemic Preconditioning; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D050863:Synaptotagmin I; D050857:Synaptotagmins; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002135:Calcium-Binding Proteins; D002518:Ceramides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D050863:Synaptotagmin I; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D050857:Synaptotagmins; D004247:DNA; D013482:Superoxide Dismutase; D017868:Cyclic AMP-Dependent Protein Kinases