Dual beta-adrenergic modulation in the immune system: stimulus-dependent effect of isoproterenol on MAPK activation and inflammatory mediator production in macrophages

Neurochem Int. 2006 Jul;49(1):94-103. doi: 10.1016/j.neuint.2006.01.009. Epub 2006 Mar 3.


This is the first study to demonstrate that the interaction between beta-adrenoceptor activation, and the production of inflammatory mediators can be modulated in opposite ways by two inflammatory stimuli, namely, protein kinase C (PKC)-activating phorbol myristyl acetate (PMA) and lipopolysaccharide (LPS). We provided evidence that isoproterenol treatment, when combined with phorbol ester increased the production of tumor necrosis factor-alpha, interleukin-12, and nitric oxide in murine macrophages, as well as in human monocytes and differentiated PLB-985 cells, while in agreement with earlier findings, it decreased inflammatory mediator production in combination with LPS stimulation. The contrasting effect on inflammatory mediator production, shown for the PMA and LPS activated cells was accompanied by parallel changes in activation of ERK1/2 and p38 MAPKs. Thus, isoproterenol significantly increased MAPK activation (phosphorylation) in PMA-treated cells and, conversely, it decreased the activation of extracellular signal regulated kinase 1/2 (ERK1/2) and p38 in LPS-stimulated cells. The opposing effects of isoproterenol on LPS-induced versus PMA-induced mediator production and the concurrent changes in MAPK activation highlight the role of this kinase pathway in macrophage activation and provide new insights regarding the flexible ways through which beta-adrenoceptor stimulation can modulate the inflammatory response in macrophages. Our results challenge the dogma that beta-adrenoceptor signaling is only immunosuppressive, and offer potential opportunities for new therapeutic approaches in the treatment of inflammatory and autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Carcinogens / pharmacology
  • Cell Line
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / immunology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Inflammation Mediators / immunology*
  • Inflammation Mediators / metabolism
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Isoproterenol / pharmacology
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / immunology*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Neuroimmunomodulation / drug effects
  • Neuroimmunomodulation / immunology*
  • Nitric Oxide / metabolism
  • Phosphorylation / drug effects
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / immunology*
  • Receptors, Adrenergic, beta / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / immunology
  • p38 Mitogen-Activated Protein Kinases / drug effects
  • p38 Mitogen-Activated Protein Kinases / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Adrenergic beta-Agonists
  • Carcinogens
  • Inflammation Mediators
  • Lipopolysaccharides
  • Receptors, Adrenergic, beta
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Nitric Oxide
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Isoproterenol
  • Tetradecanoylphorbol Acetate