β-Adrenergic agonists exert their “anti-inflammatory” effects in monocytic cells through the IκB/NF-κB pathway

TLDR

β‑adrenergic agonists possess anti‑inflammatory properties by suppressing cytokine production in human mononuclear cells. The study proposes that these effects arise from the agonists’ ability to raise cytoplasmic IκB‑α levels, likely by reducing its degradation. In LPS‑stimulated THP‑1 cells, β‑agonists lowered TNF‑α and IL‑8 secretion through β2‑adrenergic receptor–mediated cAMP/PKA signaling, inhibited late NF‑κB nuclear translocation, and promoted a rebound increase in cytosolic IκB‑α that sequestered NF‑κB in the cytoplasm.

Abstract

In addition to their well-studied bronchodilatory and cardiotonic effects, β-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 β-agonists inhibited tumor necrosis factor-α and interleukin-8 production predominantly via the β 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-κB induced by LPS were inhibited with treatment with β-agonists, an effect that was prominent at late time points (>1 h). Although the initial IκB-α degradation induced by LPS was minimally affected by β-agonists, the latter induced a marked rebound of the cytosolic IκB-α levels at later time points (>1 h), accompanied by an increased IκB-α cytoplasmic half-life. This potentially accounts for the observed nuclear factor-κB sequestration in the cytoplasmic compartment. We postulate that the anti-inflammatory effects of β-agonists reside in their capacity to increase cytoplasmic concentrations of IκB-α, possibly by decreasing its degradation.