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

Eur J Immunol. 2005 Jan;35(1):31-41. doi: 10.1002/eji.200425524.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Adenosine / metabolism*
  • Adenosine / pharmacology
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Cells, Cultured
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • I-kappa B Proteins / metabolism
  • Lectins, C-Type
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Mast Cells / drug effects
  • Mast Cells / immunology
  • Mast Cells / metabolism
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, IgG / metabolism
  • Receptors, Immunologic / metabolism*
  • Signal Transduction

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • Fcgr1 protein, mouse
  • I-kappa B Proteins
  • Lectins, C-Type
  • Lipopolysaccharides
  • NF-kappa B
  • Nfkbia protein, mouse
  • Receptors, Antigen, B-Cell
  • Receptors, IgG
  • Receptors, Immunologic
  • NF-KappaB Inhibitor alpha
  • Colforsin
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Adenosine
  • 1-Methyl-3-isobutylxanthine