α1-Adrenergic Receptors Positively Regulate Toll-Like Receptor Cytokine Production from Human Monocytes and Macrophages

Catecholamines released from the sympathetic nervous system in response to stress or injury affect expression of inflammatory cytokines generated by immune cells. alpha(1)-Adrenergic receptors (ARs) are expressed on innate immune cell populations, but their subtype expression patterns and signaling characteristics are not well characterized. Primary human monocytes, a human monocytic cell line, and monocyte-derived macrophage cells were used to measure expression of the proinflammatory mediator interleukin (IL)-1 beta responding to lipopolysaccharide (LPS) in the presence or absence of alpha(1)-AR activation. Based on our previous findings, we hypothesized that alpha(1)-AR stimulation on innate immune cells positively regulates LPS-initiated IL-1 beta production. IL-1 beta production in response to LPS was synergistically higher for both monocytes and macrophages in the presence of the selective alpha(1)-AR agonist (R)-(-)-phenylephrine hydrochloride (PE). This synergistic IL-1 beta response could be blocked with a selective alpha(1)-AR antagonist as well as inhibitors of protein kinase C (PKC). Radioligand binding studies characterized a homogenous alpha(1B)-AR subtype population on monocytes, which changed to a heterogeneous receptor subtype expression pattern when differentiated to macrophages. Furthermore, increased p38 mitogen-activated protein kinase (MAPK) activation was observed only with concurrent PE and LPS stimulation, peaking after 120 and 30 min in monocytes and macrophages, respectively. Blocking the PKC/p38 MAPK signaling pathway in both innate immune cell types inhibited the synergistic IL-1 beta increase observed with concurrent PE and LPS treatments. This study characterizes alpha(1)-AR subtype expression on both human monocyte and macrophage cells and illustrates a mechanism by which increased IL-1 beta production can be modulated by alpha(1)-AR input.