15580656

pubmed:Citation

1

Anergic B lymphocytes exert compromised signal transduction towards the activation of NF-kappa B 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-kappa B 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-kappa B 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-kappa B. 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-kappa B pathway. This suggests that adenosine-mediated signals represent an important step in the molecular decision process controlling inflammation versus anergic immune responses.

eng

IM

MEDLINE

0014-2980

Print

NLM

31-41

pubmed-meshheading:15580656-1-Methyl-3-isobutylxanthine, pubmed-meshheading:15580656-Adenosine, pubmed-meshheading:15580656-Animals, pubmed-meshheading:15580656-Antigens, CD, pubmed-meshheading:15580656-Antigens, Differentiation, T-Lymphocyte, pubmed-meshheading:15580656-B-Lymphocytes, pubmed-meshheading:15580656-Cell Line, pubmed-meshheading:15580656-Cell Survival, pubmed-meshheading:15580656-Cells, Cultured, pubmed-meshheading:15580656-Cyclic AMP, pubmed-meshheading:15580656-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:15580656-Forskolin, pubmed-meshheading:15580656-I-kappa B Proteins, pubmed-meshheading:15580656-Lectins, C-Type, pubmed-meshheading:15580656-Lipopolysaccharides, pubmed-meshheading:15580656-MAP Kinase Signaling System, pubmed-meshheading:15580656-Mast Cells, pubmed-meshheading:15580656-Mice, pubmed-meshheading:15580656-NF-kappa B, pubmed-meshheading:15580656-Phosphorylation, pubmed-meshheading:15580656-Receptors, Antigen, B-Cell, pubmed-meshheading:15580656-Receptors, IgG, pubmed-meshheading:15580656-Receptors, Immunologic, pubmed-meshheading:15580656-Signal Transduction

Adenosine and cAMP are potent inhibitors of the NF-kappa B pathway downstream of immunoreceptors.

Journal Article, Research Support, Non-U.S. Gov't