title: α1-adrenergic receptors positively regulate Toll-like receptor cytokine production from human monocytes and macrophages.
abstract: 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.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58202-9037, USA.
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Grisanti
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Woster
authors.forename: Julie
authors.initials: J
authors.lastname: Dahlman
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sauter
authors.forename: Colin K
authors.initials: CK
authors.lastname: Combs
authors.forename: James E
authors.initials: JE
authors.lastname: Porter
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000276:immunology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000502:physiology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D021122:Protein Subunits / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology*
chemical_list: C508585:IL1B protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D021122:Protein Subunits; D018340:Receptors, Adrenergic, alpha-1; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4