期刊
MOLECULAR IMMUNOLOGY
卷 47, 期 6, 页码 1244-1254出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2009.12.013
关键词
beta-Adrenergic receptors; Interleukin-1 beta; Monocytes; Receptor signaling; Catecholamines
资金
- National Science Foundation [02351461, EPS-0447679]
- National Institutes of Health [GM066726]
- National Institutes of Health Centers of Biomedical Research Excellence (COBRE) [RR016471]
Stress induced circulating catecholamines are hypothesized to selectively activate adrenergic receptors (ARs) on immunocompetent cells modulating their inflammatory response to trauma or environmental toxins. We characterized changes in expression of a pro-inflammatory cytokine modulated by beta-AR activation in human primary and immortalized monocytes that had been simultaneously stimulated with lipopolysaccharide (LPS). Results from cytokine antibody arrays demonstrated that half-maximal effective concentrations of the selective beta-AR agonist isoproterenol (Iso) qualitatively increased LPS-mediated expression of the soluble cytokine, interleukin-1 beta (IL-1 beta). Semi-quantitative immunoblot techniques confirmed a synergistic increase of IL-1 beta production in both LPS stimulated THP-1 cells and primary human monocytes co-incubated with Iso. Immunoblot techniques as well as radioligand binding studies were also used to characterize the heterogeneous expression of beta(1)- and beta(2)-AR subtypes on THP-1 cells. beta-AR activation is classically associated with generation of cAMP in many tissues and cell types. Therefore, using the method of Schild, we generated Iso concentration-response curves in the presence of fixed subtype-selective beta-AR antagonist concentrations to demonstrate that beta(1)-AR activation was exclusively linked with the generation of cAMP in THP-1 cells. Furthermore, use of a selective kinase inhibitor demonstrated that Is potentiated the expression of soluble IL-1 beta through activation of cAMP-dependent protein kinase A. Finally, discriminating concentrations of subtype-selective beta-AR antagonists revealed that beta(1)-AR stimulation alone accounted for the synergistic production of IL-1 beta in LPS stimulated monocytes co-incubated with Is. These results demonstrate a unique synergistic pro-inflammatory response mediated through a beta(1)-AR cAMP-dependent mechanism in LPS-challenged monocytic cells. (C) 2010 Elsevier Ltd. All rights reserved.
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