β₁‐Adrenergic Receptor Activation Potentiates a Pro‐Inflammatory Response in Human Monocytes

Abstract

Increased circulating catecholamines released from the sympathetic nervous system, selectively activate immune cell receptors, modulating their inflammatory response to stress, injury or environmental toxins. Human monocytic THP‐1 cells were used to measure expression of inflammatory mediators responding to β‐adrenergic receptor (AR) activation in the presence or absence of lipopolysaccharide (LPS). Results from antibody arrays demonstrated that effective concentrations of the selective β‐AR agonist isoproterenol (Iso) synergistically increased LPS‐mediated expression of interleukin‐1β (IL‐1β) in THP‐1 cells. Selective kinase inhibition demonstrated that this β‐AR‐mediated, synergistic IL‐1β response signaled through activation of cAMP‐dependent protein kinase A. Radioligand binding studies further characterized a heterogeneous β‐AR population expressed on these same cells. Schild analysis demonstrated that only the β1‐AR subtype was responsible for generating cAMP in response to Iso. Furthermore, discerning concentrations of subtype‐selective β‐AR antagonists revealed that β1‐AR subtype activation facilitated this potentiated increase in IL‐1β production. Synergistic pro‐inflammatory responses in THP‐1 cells mediated by β1‐AR subtype coupling to cAMP‐dependent protein kinase A, represents a mechanism by which autonomic outflow could modulate immune function in vivo. Funding: NSF Grant 0235146