α1-Adrenergic Receptors Positively Regulate Toll-Like Receptor Cytokine Production from Human Monocytes and Macrophages
α1-Adrenergic Receptors Positively Regulate Toll-Like Receptor Cytokine Production from Human Monocytes and Macrophages
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DOI：
10.1124/jpet.110.178012
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发表时间：
2011-08-01
影响因子：
3.5
通讯作者：
Porter, James E.
中科院分区：
文献类型：
--
作者：
Grisanti, Laurel A.;Woster, Andrew P.;Porter, James E.
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.
