Anergic B lymphocytes exert compromised signal transduction towards the activation of NF‐κB in response to B cell antigen receptor (BCR) triggering, whereas activation of the ERK pathway appears normal. How this differential down‐regulation of the NF‐κB pathway is regulated remains still elusive. Here, we demonstrate that stimuli known to enhance 3′,5′‐cyclic adenosine monophosphate (cAMP) are capable of selectively suppressing the activation both of NF‐κB downstream of the BCR and Toll‐like receptor 4 in splenic B lymphocytes and of the high‐affinity receptor for IgE in BM‐derived mast cells. This suppression is accomplished by blocking phosphorylation and subsequent degradation of the inhibitor of NF‐κB. A cAMP‐dependent protein kinase (PKA) inhibitor reverses this suppressive effect, indicating that PKA is a downstream effector of cAMP in this process. Importantly, not only drugs that artificially elevate intracellular cAMP levels, but also the nucleoside adenosine, which is known to be a mediator of cellular distress, inhibit the NF‐κB pathway. This suggests that adenosine‐mediated signals represent an important step in the molecular decision process controlling inflammation versus anergic immune responses.

See accompanying Commentary: http://dx.doi.org/10.1002/eji.200425738