This project is focused on the identification of physiologically critical functions and mechanisms of action of NF-kB transcription factors and their regulators in health and disease. NF-kB is a family of related dimeric transcription factors that serve as primary intracellular mediators during innate and adaptive immune responses. In addition, and importantly, aberrant regulation of NF-kB plays a major role in inflammatory and autoimmune diseases as well as in numerous tumors. It is thus imperative to understand the functions and mechanisms of action of individual NF-kB factors and their regulators, as this will be required to devise appropriate strategies for therapeutic interventions aimed at curtailing aberrantly regulated NF-kB in a precisely targeted manner. To identify physiologic roles and mechanisms we make use of mouse models engineered to lack components of the NF-kB transcription factor family or their regulators, as well as models in which the NF-kB factors can be selectively activated. Our work is focused on alternatively and classically activated NF-kB factors, and especially on Bcl-3. The alternative NF-kB activation pathway is normally initiated by a subset of TNF receptors. Bcl-3 is an atypical IkB family member that functions as nuclear regulator of NF-kB activity. In the recent past we have demonstrated critical roles for Bcl-3 in normal late differentiation of B cells into marginal and follicular B cells. IN FY 2014 we have now discovered an unexpected critical role for Bcl-3 in dendritic cells. Bcl-3 was required in dendritic cells for proper presentation of antigens to T cells to prime them for proliferation. Priming of T cells by dendritic cells is crucial to initiate adaptive immune responses. We demonstrate that rather than playing a major role in the maturation of B cells or the physical processing of antigens and the presentation of resulting peptides to T cells, Bcl-3 was most critical for the survival of dendritic cells;in the absence of Bcl-3 the dendritic cells did not survive long enough to assure proper continued activation and expansion of T cells. Bcl-3 appeared to contribute to the expression of several anti-apoptotic genes in dendritic cells. We demonstrated this in vitro, but were also able confirm that this also occurred in vivo. As part of our in vivo studies we showed that the impaired priming of T cells by dendritic cells ameliorated the severity of inflammation in a contact hypersensitivity model;in this model sensitization to haptens on dorsal skin patches leads to a subsequent hypersensitive inflammatory reaction at a distal skin site. In FY 2014 we also established models to explore the role of Bcl-3 in T cells in autoimmune contexts, and we continued to explore the roles of this NF-kB regulator in the contexts of tumor development in B cells as well as other cells.

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Das, Nitin A; Carpenter, Andrea J; Yoshida, Tadashi et al. (2018) TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. J Mol Cell Cardiol 121:107-123
Erikson, John M; Valente, Anthony J; Mummidi, Srinivas et al. (2017) Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling. J Biol Chem 292:2345-2358
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Low, J T; Hughes, P; Lin, A et al. (2015) Impact of loss of NF-?B1, NF-?B2 or c-REL on SLE-like autoimmune disease and lymphadenopathy in Fas(lpr/lpr) mutant mice. Immunol Cell Biol :
O'Reilly, L A; Hughes, P; Lin, A et al. (2015) Loss of c-REL but not NF-?B2 prevents autoimmune disease driven by FasL mutation. Cell Death Differ 22:767-78
Kanno, Tomohiko; Kanno, Yuka; LeRoy, Gary et al. (2014) BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones. Nat Struct Mol Biol 21:1047-57

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