A novel mechanism of control of NFκB activation and inflammation involving A_2B adenosine receptors

The nuclear factor kappa B (NFκB) pathway controls a variety of processes, including inflammation, and thus, the regulation of NFκB has been a continued focus of study. Here, we report a newly identified regulation of this pathway, involving direct binding of the transcription factor NFκB1 (the p105 subunit of NFκB) to the C-terminus of the A_2B adenosine receptor (A_2BAR), independent of ligand activation. Intriguingly, binding of A_2BAR to specific sites on p105 prevents polyubiquitylation and degradation of p105 protein. Ectopic expression of the A_2BAR increases p105 levels and inhibits NFκB activation, whereas p105 protein levels are reduced in cells from A_2BAR-knockout mice. In accordance with the known regulation of expression of anti- and pro-inflammatory cytokines by p105, A_2BAR-null mice generate less interleukin (IL)-10, and more IL-12 and tumor necrosis factor (TNF-α). Taken together, our results show that the A_2BAR inhibits NFκB activation by physically interacting with p105, thereby blocking its polyubiquitylation and degradation. Our findings unveil a surprising function for the A_2BAR, and provide a novel mechanistic insight into the control of the NFκB pathway and inflammation.