Tumor necrosis factor-α activation of nuclear transcription factor-κB in marrow macrophages is mediated by c-Src tyrosine phosphorylatiola of IκBα

Tumor necrosis factor-alpha (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-kappa B (NF-kappa B), NF-kappa B is sequestered in the cytosol by I kappa B alpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation. In contrast, we find TNF induction of NF-kappa B in murine bone marrow macrophages (BMMs), is mediated, by c-Src, in a cell, and cytokine specific manner. The non-receptor tyrosine kinase is rapidly mobilized and activated upon TNF exposure. Within the same time frame, TNF induced c-Src associates with I kappa B alpha in a long lived complex. The proto-oncogene, when associated with I kappa B alpha phosphorylates the inhibitory protein on tyrosine 42. Consistent with the pivotal role played by c-Src in TNF-induced I kappa B alpha tyrosine phosphoryhtion, NF-kappa B activation, by the cytokine, is markedly delayed and reduced in c-src-/-BMMs. Underscoring the physiological significance of c-Src activation of NF-kappa B, TNF induction of IL-6, which is an NF-kappa B mediated event, is substantially diminished in c-src-/-BMMs.