β2-receptor agonists salbutamol and terbutaline attenuated cytokine production by suppressing ERK pathway through cAMP in macrophages.
β2-receptor agonists are used in the treatment of inflammatory obstructive lung diseases asthma and COPD as a symptomatic remedy, but they have been suggested to possess anti-inflammatory properties, also. β2-receptor activation is considered to lead to the activation of ERK pathway through G-protein- and cAMP-independent mechanisms. In this study, we investigated the effects of β2-receptor agonists salbutamol and terbutaline on the production of inflammatory factors in macrophages. We found that β2-receptor agonists inhibited LPS-induced ERK phosphorylation and the production of MCP-1. A chemical cAMP analog 8-Br-cAMP also inhibited ERK phosphorylation and TNF and MCP-1 release. As expected, MAPK/ERK kinase (MEK)1/2 inhibitor PD0325901 inhibited ERK phosphorylation and suppressed both TNF and MCP-1 production. In conclusion, we suggest that β2-receptor agonists salbutamol and terbutaline inhibit inflammatory gene expression partly by a mechanism dependent on cAMP leading to the inhibition of ERK signaling in macrophages. Observed anti-inflammatory effects of β2-receptor agonists may contribute to the clinical effects of these drugs.
The Immunopharmacology Research Group, University of Tampere School of Medicine, and Tampere University Hospital, Tampere, Finland.
Tiina
T
Keränen
The Immunopharmacology Research Group, University of Tampere School of Medicine, and Tampere University Hospital, Tampere, Finland.
Tuija
T
Hömmö
The Immunopharmacology Research Group, University of Tampere School of Medicine, and Tampere University Hospital, Tampere, Finland.
Eeva
E
Moilanen
The Immunopharmacology Research Group, University of Tampere School of Medicine, and Tampere University Hospital, Tampere, Finland. Electronic address: riku.korhonen@staff.uta.fi.
Riku
R
Korhonen
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D008163:Luminescent Measurements; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D013726:Terbutaline / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D001549:Benzamides; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; D015124:8-Bromo Cyclic Adenosine Monophosphate; C506614:mirdametinib; D004159:Diphenylamine; C044258:8-chloro-cyclic adenosine monophosphate; D000242:Cyclic AMP; D013726:Terbutaline; D000420:Albuterol
ERK; MCP-1; Macrophage; Salbutamol; TNF; β(2)-adrenergic receptor