Bacterial LPS and IFN-gamma trigger the tyrosine phosphorylation of vav in macrophages: evidence for involvement of the hck tyrosine kinase.

We and others have previously reported that tyrosine kinases play key roles in the activation of macrophages by both bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). However, little is known regarding the substrates of tyrosine phosphorylation that mediate macrophage activation and the resultant production of inflammatory mediators. In lymphocytes and other hematopoietic lineages, tyrosine phosphorylation of the proto-oncogene vav appears to be an essential component of cell activation. In this study, we demonstrate that both LPS and rIFN-gamma trigger the prompt, dose-dependent tyrosine phosphorylation of vav in murine RAW 264.7 macrophages. In addition, vav is physically associated with the src-related kinase hck in murine macrophages, and antisense oligonucleotides specific for murine hck block both LPS and rIFN-gamma-mediated vav phosphorylation. These findings suggest that hck probably mediates vav tyrosine phosphorylation during macrophage activation and that LPS and rIFN-gamma-mediated signaling pathways partially overlap.