Catecholamines released from the sympathetic nervous system in response to stress or injury impact expression of inflammatory cytokines generated by immune cells. α1-Adrenergic receptors (AR) 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 pro-inflammatory mediator interleukin (IL)-1β responding to lipopolysaccharide (LPS) in the presence or absence of α1-AR activation. Based on our previous findings, we hypothesized that α1-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 α1-AR agonist, phenylephrine (PE). This synergistic IL-1β response could be blocked with a selective α1-AR antagonist as well as inhibitors of protein kinase C (PKC). Radioligand binding studies characterized a homogenous α1B-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 α1-AR subtype expression on both human monocyte as well as macrophage cells and illustrates a mechanism by which increased IL-1β production can be modulated by α1-AR input.
- Received December 8, 2010.
- Revision received April 10, 2011.
- Accepted May 12, 2011.
- The American Society for Pharmacology and Experimental Therapeutics