NF-kB activation and function in B lymphocytes

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

The NF-B family of transcription factors are stress sensors in a wide variety of cell types. Their nuclear expression can be induced in response to diverse stimuli including reactive oxygen species (ROS), DNA damage, endoplasmic reticulum (ER) stress, and inflammatory cytokines such as TNF and IL-1. NF-B target genes include inflammatory cytokines such as IL-6, TNF and IL-1, cell adhesion molecules, and molecules involved in maintenance of cell viability. The fundamental goal of our studies is to identify molecular mechanisms that underlie cell-specificity and stimulus-specificity of NF-B-dependent gene expression. In some cell systems NF-B has been shown to intersect with functions of the general transcription factor GTFIIi. Thus, in parallel, we explore the role of GTFIIi-driven transcription in B and T lymphocytes. During FY23 we accomplished the following: A manuscript describing studies identifying Rel and RelA target genes in B cells activated via the B cell receptor was published. These studies were followed up by kinetic analyses of gene expression in response to BCR signaling in purified marginal zone (MZ) and follicular (Fo) B cell subsets. NF-kB dependency will be evaluated by inhibiting IKKb, the kinase responsible for canonical NF-kB signaling in B cells. At the same time we are generating conditional double (Rel and RelA) knockout mice to genetically validate t results of pharmacological NF-kB inhibition. Stimulus specificity of NF-kB responses in MZ and Fo B cells is being evaluated using TLR4 and 9 ligands to activate each kind of B cell subset. We completed a study on the role of role transcription factor TFII-I in murine B cells. this study was accepted for publication. We are extending these studies by identifying direct targets of TFII-I and the intersection of this pathway with NF-kB.