ABSTRACT
Adrenergic signalling of the immune system is one of the important modulator pathways of the inflammatory immune response realized via G protein-mediated pathways. The resulted signal depends on the type of the receptor-coupled G-protein (GPCR) that, according to the classical paradigm in the case of beta-adrenergic receptor (beta-AR), is Gs-type. Recently, alternate and/or multiple G protein coupling specificity of GPCRs have been demonstrated including a switch from Gs to Gi binding. The possibility of a Gs/Gi switch and its role in the immune response of macrophages has not been investigated yet. In this study, we demonstrate that beta-adrenergic stimulation itself is able to induce a transient mitogen-activated protein kinase phosphorylation in murine peritoneal macrophages in a pertussis toxin-sensitive manner, suggesting that the Gs/Gi switch also occurs in the immune system. Although this process is very rapid, it can influence different signalling pathways and can reprogramme effector functions suggesting that sympathetic modulation of the defence mechanism of the innate immune system has an additional, Gs/Gi switch-dependent component.
Subject(s)
GTP-Binding Proteins/metabolism , Macrophages, Peritoneal/metabolism , Receptors, Adrenergic, beta/metabolism , Adrenergic beta-Agonists/pharmacology , Animals , Enzyme Activation/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , GTP-Binding Protein alpha Subunits, Gs/metabolism , Isoproterenol/pharmacology , Lipopolysaccharides/immunology , Macrophages, Peritoneal/immunology , Mice , Mice, Inbred BALB C , Pertussis Toxin/immunology , Phosphorylation/drug effects , Signal Transduction/immunology , Tetradecanoylphorbol Acetate/immunology , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
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.
Subject(s)
Inflammation Mediators/immunology , MAP Kinase Signaling System/immunology , Macrophages/immunology , Neuroimmunomodulation/immunology , Receptors, Adrenergic, beta/immunology , 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/metabolism , Interleukin-12/immunology , Interleukin-12/metabolism , Isoproterenol/pharmacology , Lipopolysaccharides/pharmacology , MAP Kinase Signaling System/drug effects , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Neuroimmunomodulation/drug effects , Nitric Oxide/metabolism , Phosphorylation/drug effects , Receptors, Adrenergic, beta/drug effects , 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/metabolismABSTRACT
Basic and clinical studies have provided evidence that the biophase level of monoamines, determined by the balance of their release and uptake, is involved in the pathophysiology and treatment of depression, whereas other arguments cite the role of inflammatory mediators in the etiology of psychiatric disorders. A bidirectional interaction between the monoamine system and the inflammatory system might explain the concurrent therapeutical efficacy and immunomodulatory features of antidepressants.
