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Keywords
NK-KB, LYMPHOCYTES, DENDRITIC CELLS, INFLAMMATION, APOPTOSIS, COSTIMULATION, SEPSIS

NF-kB transcription factor in the control of cell death and differentiation of the immune system.

Università degli Studi del Sannio di Benevento
Abstract
Signaling leading to the survival, differentiation or apoptosis of immune system cells must be balanced to ensure the normal mounting and extinguishing of immune responses. One of the essential regulators of immune cell survival is the transcription factor NF-kB, which is critical for the activation of T and B lymphocytes and is a central coordinator of innate and adaptive immunity.
Upon infection, pathogenic micro-organisms activate NF-?B transcription factors via triggering of Toll-like receptors, which are expressed on cells of the innate immune system, including macrophages, dendritic cells and mucosal epithelial cells. NF-?B induction is essential for the expression of a wide variety of immuneresponse genes. During the adaptive phase of an immune response, NF-?B is involved in the activation of T and B-lymphocytes by their antigen and co-stimulatory receptors. NF-?B also plays an important role in regulating the expression of anti-apoptotic proteins and the cell-cycle regulator cyclin D1, which increase cellular survival and proliferation respectively.
Consequently NF-?B has been implicated in cell transformation, and persistent NF-?B activation may explain the known causative link between chronic inflammation and certain types of cancer. Finally, NF-kB activation is a central event leading to the activation of complex cytokine and inflammatory mediator networks that results in the pathophysiology of sepsis and septic shock.

Aims of the >>>

Principal Investigator
Pasquale Vito Università degli Studi del SANNIO di BENEVENTO
Research Objectives
The transcription factor NF-kB is critical for the activation of T and B lymphocytes, is a central coordinator of innate and adaptive immunity, it controls differentiation of activated lymphocytes and it regulates cell death of immune system cells. As a consequence of this pleiotropic activity, deregulated NF-kB activation has been associated with autoimmune, limphoproliferative and inflammatory disorders. The objectives here described aim to the identification and characterization of common biochemical pathways that may possibly represent novel therapeutic targets, especially for those pathologies where the contribution of NF-kB is well established.


Specific aims of this proposal are to:

• provide a comprehensive assessment of the involvement of TRAF1, p64 and p40 in the activation of NF-kB transcription factor following antigen receptor stimulation.
Both T and B lymphocytes utilize common downstream adapter molecules to activate NF-kB, which include BCL10 and CARMA1 (1). We have recently shown that CARMA1 associates to IKKg/NEMO in lymphoid cells, and participates to an inducible large molecular complex which contains IKKg/NEMO, BCL10 and IKKa/b kinases (2). In order to identify proteins that associate to CARMA1 and BCL10 and that may regulate the activation of NF-kB, we have performed a pull-down assay, using recombinant CARMA as a bait, followed by a spectrometric analysis for the identification of CARMA-associated proteins >>>

Timescale
24 months
National and international background
The NF-kB family
The acquired immune response to foreign antigens involves the generation of a pool of effector cells through a process of activation, proliferation and differentiation, followed by lymphocyte death. Each of these biological processes requires the activation of various inducible transcription factors, among them NF-kB plays a central role. NF-kB, in fact, controls expression of a number of genes that coordinate both the innate and the adaptive immune response (1,12,13). NF-kB family of transcription factors consists of five members, including NF-kB1 (p50 and its precursor p105), NF-kB2 (p52 and its precursor p100), RelA (p65), RelB and c-Rel. The NF-kB members form homo- or heterodimers, with different regulatory functions and transcriptional activities (12,13). NF-kB1 (p50) and NF-kB2 (p52) lack transcriptional activation domains, but show a higher DNA binding affinity when compared to Rel-A, Rel-B, and c-Rel, which carry the TA domains. Indeed, p50 and p52 homo-dimers are thought to act as repressors. The balance between different NF-kB homo- and hetero-dimers as well as covalent modifications of NF-kB subunits, will determine the preferential binding and activity of NF-kB dimers on the target gene promoters (12,13). NF-kB activity is regulated by a protein kinase complex, known as IKK signalosome, that phosphorylates inhibitory proteins belonging to the IkB family (IkBalpha, IkBbeta and IkBepsilon), thus leading to their proteolytic degradation and >>>