NF-kB activation and function in B lymphocytes

National Institute On Aging

Investigators

Abstract

During the present fiscal year (2008) we accomplished the following:[unreadable] [unreadable] (1) Devised a pulsed activation strategy to investigate the consequences of a single round of BCR signaling. We found that this form of stimulation induced cell death from an early G1 checkpoint.[unreadable] [unreadable] (2) All cytoplasmic signaling cascades, including NF-κB, were normally activated after pulsed stimulation except the PI3 kinase/Akt pathway, which was induced transiently. However, cells did not progress into G1. [unreadable] [unreadable] (3) Analysis of mRNA isolated at various times following pulsed or continuous activation revealed long-term changes in cells that had been activated through only one round of BCR cross-linking. Those included up- and down-regulated genes. We hypothesize that the gene patterns we have identified reflect the preliminary response of B cells on their way towards T-dependent activation.[unreadable] [unreadable] (4) We found that pulsed activated B cells were primed to receive CD40 signals; when stimulated secondarily with anti-CD40 these cells responded 3-4x fold more effectively as measured by increased cell size, increased phosphorylation of retinoblastoma protein and increased expression of cyclin D2. We surmise that priming is the consequence of altered gene expression patterns induced by single-round BCR stimulation.