beta-adrenergic agonists exert their "anti-inflammatory" effects in monocytic cells through the IkappaB/NF-kappaB pathway.
In addition to their well-studied bronchodilatory and cardiotonic effects, beta-adrenergic agonists carry anti-inflammatory properties by inhibiting cytokine production by human mononuclear cells. In a model of human promonocytic THP-1 cells stimulated with lipopolysaccharide (LPS), we showed that beta-agonists inhibited tumor necrosis factor-alpha and interleukin-8 production predominantly via the beta(2)-adrenergic receptor through the generation of cAMP and activation of protein kinase A. This effect was reproduced by other cAMP-elevating agents such as prostaglandins and cAMP analogs. Activation and nuclear translocation of the transcription factor nuclear factor-kappaB induced by LPS were inhibited with treatment with beta-agonists, an effect that was prominent at late time points (>1 h). Although the initial IkappaB-alpha degradation induced by LPS was minimally affected by beta-agonists, the latter induced a marked rebound of the cytosolic IkappaB-alpha levels at later time points (>1 h), accompanied by an increased IkappaB-alpha cytoplasmic half-life. This potentially accounts for the observed nuclear factor-kappaB sequestration in the cytoplasmic compartment. We postulate that the anti-inflammatory effects of beta-agonists reside in their capacity to increase cytoplasmic concentrations of IkappaB-alpha, possibly by decreasing its degradation.
Farmer
P
P
Division of Medical Intensive Care, Department of Internal Medicine, University Hospital of Geneva, 1211 Geneva 14, Switzerland.
Pugin
J
J
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D004789:Enzyme Activation; D004837:Epinephrine / Q000494:pharmacology; D005280:Fenoterol / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins; D016285:Iloprost / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D005280:Fenoterol; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D016285:Iloprost; D015232:Dinoprostone; D007545:Isoproterenol; D000420:Albuterol; D009638:Norepinephrine; D004837:Epinephrine