α1-adrenergic receptors positively regulate Toll-like receptor cytokine production from human monocytes and macrophages

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 338; no. 2; pp. 648 - 657
• Main Authors: Grisanti, Laurel A, Woster, Andrew P, Dahlman, Julie, Sauter, Edward R, Combs, Colin K, Porter, James E
• Format: Journal Article
• Language: English
• Published: United States The American Society for Pharmacology and Experimental Therapeutics 01.08.2011
• Subjects: Adult; Cell Differentiation - immunology; Cell Line, Transformed; Cells, Cultured; Humans; Immunity, Innate; Inflammation Mediators - physiology; Inflammation, Immunopharmacology, and Asthma; Interleukin-1beta - biosynthesis; Interleukin-1beta - blood; Lipopolysaccharides - physiology; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Monocytes - immunology; Monocytes - metabolism; Monocytes - pathology; Protein Subunits - biosynthesis; Protein Subunits - blood; Protein Subunits - physiology; Receptors, Adrenergic, alpha-1 - biosynthesis; Receptors, Adrenergic, alpha-1 - blood; Receptors, Adrenergic, alpha-1 - physiology; Signal Transduction - immunology; Toll-Like Receptor 4 - biosynthesis; Toll-Like Receptor 4 - blood; Toll-Like Receptor 4 - physiology; Up-Regulation - immunology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.178012

Catecholamines released from the sympathetic nervous system in response to stress or injury affect expression of inflammatory cytokines generated by immune cells. α(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)-1β responding to lipopolysaccharide (LPS) in the presence or absence of α(1)-AR activation. Based on our previous findings, we hypothesized that α(1)-AR stimulation on innate immune cells positively regulates LPS-initiated IL-1β production. IL-1β production in response to LPS was synergistically higher for both monocytes and macrophages in the presence of the selective α(1)-AR agonist (R)-(-)-phenylephrine hydrochloride (PE). This synergistic IL-1β response could be blocked with a selective α(1)-AR antagonist as well as inhibitors of protein kinase C (PKC). Radioligand binding studies characterized a homogenous α(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-1β increase observed with concurrent PE and LPS treatments. This study characterizes α(1)-AR subtype expression on both human monocyte and macrophage cells and illustrates a mechanism by which increased IL-1β production can be modulated by α(1)-AR input.