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NF-B Is Required for Surface Ig-Induced Fas Resistance in B Cells¹

Brian R. Schram^*, and Thomas L. Rothstein^2,*,,

Departments of ^* Microbiology and Medicine, Boston University School of Medicine, and Immunobiology Unit, Evans Memorial Department of Clinical Research, Boston University Medical Center, Boston, MA 02118

The susceptibility of primary murine B cells to Fas-mediated apoptosis is regulated in a receptor-specific fashion. Whereas CD40 engagement produces marked sensitivity to Fas killing, engagement of the B cell Ag receptor blocks Fas signaling for cell death in otherwise Fas-sensitive, CD40-stimulated targets and thus induces Fas resistance. The signaling pathway that leads from B cell Ag receptor to Fas resistance has not been fully characterized, but has been shown to depend on new gene expression. NF-B is activated following B cell Ag receptor engagement and is associated with antiapoptosis; thus, it would seem a likely candidate to mediate transcriptional activation for inducible Fas resistance. Inhibition of B cell Ag receptor signaling for NF-B activation completely blocked induction of Fas resistance by anti-Ig, and this same phenotype was observed both with chemical inhibitors such as lactacystin and pyrrolidinedithiocarbamate as well as with an IB dominant negative TAT fusion protein. Antiapoptotic, NF-B-responsive transcripts include two gene products previously implicated in mediating anti-Ig-induced Fas resistance, Bcl-x_L and FLIP. B cell Ag receptor-induced up-regulation of both these gene products was blocked by NF-B inhibition, suggesting a mechanism by which the loss of nuclear NF-B alters the sensitivity of B cell Ag receptor-stimulated B cells to Fas-mediated apoptosis. These results indicate that activation of NF-B plays a key role in mediating Fas resistance produced by B cell Ag receptor engagement.

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