TNF-α–Induced Tolerance to Ischemic Injury Involves Differential Control of NF-κB Transactivation: The Role of NF-κB Association with p300 Adaptor

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Abstract
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-α) has been implicated in development of ischemic tolerance. Using cellular models of ischemic tolerance, we have demonstrated that an effector of TNF-α– induced preconditioning is ceramide, a sphingolipid messenger in TNF-α signaling. TNF-α/ceramide-induced preconditioning protected cultured neurons against ischemic death and cultured astrocytes against proinflammatory effects of TNF-α. TNF-α activates a transcription factor NF-κB that binds promoters of multiple genes, thus ensuring pleiotropic effects of TNF-α. We describe here a mechanism that allows selective suppression of TNF-α/NF-κB–induced harmful genes in preconditioned cells while preserving cytoprotective responses. We demonstrate that in astrocytes activation of an adhesion molecule ICAM-1 by TNF-α is regulated through association of the phosphorylated p65 subunit of NF-κB with an adapter protein, p300, and that in preconditioned cells p65 remains unphosphorylated and ICAM-1 transcription is inhibited. However, TNF-α–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-α–induced adaptation to ischemic stress and inflammation could suggest novel avenues for clinical intervention during ischemic and inflammatory diseases.