Synergistic activation of NF- mu B by tumor necrosis factor alpha and gamma interferon via enhanced I mu B alpha degradation and de novo I mu B beta degradation

Tumor necrosis factor alpha (TNF- alpha ) and gamma interferon (IFN- gamma ) are required for an effective immune response to bacterial infection and these cytokines synergize in a variety of biological responses, including the induction of cytokine, cell adhesion, and inducible nitrous oxide synthase gene expression. Typically, the synergistic effect on gene expression is due to the independent activation of nuclear factor Kappa B (NF- Kappa B) by TNF- alpha and of signal transducers and activators of transcription or IFN-regulatory factor 1 by IFNs, allowing these transcription factors to bind their unique promoter sites. However, since activation of NF- Kappa B by TNF- alpha is often transient and would not activate long-term Kappa B-dependent transcription effectively, we explored the effects of IFN- gamma on TNF- alpha -induced NF- Kappa B activity. IFN- gamma , which typically does not activate NF- Kappa B, synergistically enhanced TNF- alpha -induced NF- Kappa B nuclear translocation via a mechanism that involves the induced degradation of I Kappa B beta and that apparently requires tyrosine kinase activity in preneuronal cells but not in endothelial cells. Correspondingly, cotreatment of cells with TNF- alpha and IFN- gamma leads to persistent activation of NF- Kappa B and to potent activation of Kappa B-dependent gene expression, which may explain, at least in part, the synergy observed between these cytokines, as well as their involvement in the generation of an effective immune response.