A novel mechanism of control of NF?B activation and inflammation involving A2B adenosine receptors.

ABSTRACT: The nuclear factor kappa B (NF?B) pathway controls a variety of processes, including inflammation, and thus, the regulation of NF?B has been a continued focus of study. Here, we report a newly identified regulation of this pathway, involving direct binding of the transcription factor NF?B1 (the p105 subunit of NF?B) to the C-terminus of the A(2B) adenosine receptor (A(2B)AR), independent of ligand activation. Intriguingly, binding of A(2B)AR to specific sites on p105 prevents polyubiquitylation and degradation of p105 protein. Ectopic expression of the A(2B)AR increases p105 levels and inhibits NF?B activation, whereas p105 protein levels are reduced in cells from A(2B)AR-knockout mice. In accordance with the known regulation of expression of anti- and pro-inflammatory cytokines by p105, A(2B)AR-null mice generate less interleukin (IL)-10, and more IL-12 and tumor necrosis factor (TNF-?). Taken together, our results show that the A(2B)AR inhibits NF?B activation by physically interacting with p105, thereby blocking its polyubiquitylation and degradation. Our findings unveil a surprising function for the A(2B)AR, and provide a novel mechanistic insight into the control of the NF?B pathway and inflammation.

SUBMITTER: Sun Y 

PROVIDER: S-EPMC3500865 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other