β-Adrenergic agonists exert their "anti-inflammatory" effects in monocytic cells through the IκB/NF-κB 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-kappa B induced by LPS were inhibited with treatment with beta-agonists, an effect that was prominent at late time points (>1 h). Although the initial I kappa B-alpha degradation induced by LPS was minimally affected by beta-agonists, the latter induced a marked rebound of the cytosolic I kappa B-alpha levels at later time points (>1 h), accompanied by an increased I kappa B-alpha cytoplasmic half-life. This potentially accounts for the observed nuclear factor-kappa B sequestration in the cytoplasmic compartment. We postulate that the anti-inflammatory effects of beta-agonists reside in their capacity to increase cytoplasmic concentrations of I kappa B-alpha, possibly by decreasing its degradation.