TUMOR-NECROSIS-FACTOR-ALPHA ACTIVATION OF NUCLEAR TRANSCRIPTION FACTOR-KAPPA-B IN MARROW MACROPHAGES IS MEDIATED BY C-SRC TYROSINE PHOSPHORYLATIOLA OF I-KAPPA-B-ALPHA

Tumor necrosis factor-alpha (TNF) exerts its transcriptional effects v ia 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 protei n which then undergoes rapid, ubiquitin-dependent degradation. In cont rast, we find TNF induction of NF-kappa B in murine bone marrow macrop hages (BMMs), is mediated, by c-Src, in a cell, and cytokine specific manner. The non-receptor tyrosine kinase is rapidly mobilized and acti vated 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-on cogene, when associated with I kappa B alpha phosphorylates the inhibi tory protein on tyrosine 42. Consistent with the pivotal role played b y c-Src in TNF-induced I kappa B alpha tyrosine phosphoryhtion, NF-kap pa B activation, by the cytokine, is markedly delayed and reduced in c -src-/-BMMs. Underscoring the physiological significance of c-Src acti vation of NF-kappa B, TNF induction of IL-6, which is an NF-kappa B me diated event, is substantially diminished in c-src-/-BMMs.