ANTIGEN-RECEPTOR ENGAGEMENT IN B-CELLS INDUCES NUCLEAR EXPRESSION OF STAT5 AND STAT6 PROTEINS THAT BIND AND TRANSACTIVATE AN IFN-GAMMA ACTIVATION SITE

The signal transducer and activator of transcription (STAT) family of transcription factors is triggered by cytokine and growth factor recep tors in a number of cell types, and binds to a consensus sequence defi ned in part by the IFN-gamma activation site (GAS). It is not known wh ether these transcription factors respond to other kinds of growth sti muli, and, with particular relevance to lymphocytes, it is not known w hether STAT proteins participate in Ag-specific responses. To determin e the role of STAT proteins, coupling between Ag-receptor cross-linkin g and nuclear expression of DNA-binding protein complexes that recogni ze GAS sequences was evaluated. Ag-receptor triggering in primary B ly mphocytes stimulated nuclear expression of a complex that specifically binds the IFN response factor-1 (IRF-1) GAS sequence, and is distingu ished by electrophoretic mobility and GAS preference from IRF-1 GAS-bi nding complexes induced by IFN-gamma. Activation of nuclear IRF-1 GAS- binding activity by sig was inhibited by the tyrosine kinase inhibitor , herbimycin A, and binding activity was eliminated by tyrosine phosph atase treatment. Activation of IRF-1 GAS-binding activity was blocked by depletion of protein kinase C. The IRF-1 GAS-binding activity induc ed by sig engagement in B cells was transcriptionally active, and was found to consist of immunoreactive STAT5 and STAT6 proteins. This work demonstrates that the STAT signaling pathway previously associated wi th cytokine signaling is triggered in B lymphocytes through Ag-recepto r engagement in a protein kinase C-dependent fashion. This heretofore described cytokine signaling pathway may play a role in bringing about Ag-specific proliferative and differentiative responses.